JP2005522436A - Piperidylcarboxamide derivatives or their use in the treatment of tachykinin-mediated diseases - Google Patents

Abstract

The present invention provides compounds of formula (I) wherein R is halogen or C _1-4 alkyl; R ₁ is hydrogen or C _1-4 alkyl; R ₂ is hydrogen, C _1-4 alkyl, or R ₂ Together with R ₃ represents C _3-7 cycloalkyl; R ₃ is hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-6 alkenyl; or R ₁ and R ₃ Represents a 5- to 6-membered heterocyclic group together with the nitrogen and carbon atoms to which they are respectively attached; R ₄ represents trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethoxy or halogen R ₅ is hydrogen and R ₆ is NR ₇ R ₈ or R ₅ is NR ₈ R ₉ and R ₆ is hydrogen; R ₇ is hydrogen or C _1-4 alkyl; Or R ₇ and R ₈ are bonded Together with the combined nitrogen represents an oxygen-containing saturated 5- to 7-membered heterocyclic group; R ₈ is hydrogen, phenyl, C _3-7 cycloalkyl, (CH ₂ ) _p C (O) NR ₁₀ R _11. Saturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen (C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C ( O) optionally substituted with C _1-4 alkyl), a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen (C _1-4 alkyl S (O ) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl), or R ₈ is a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms (C _1-4 alkyl, S (O) ₂ C _1-4 a Or optionally substituted with C (O) C _1-4 alkyl); or R ₈ is substituted with fluorine, phenyl (C _1-4 alkyl, C (O) C _1-4 alkyl or halogen). Substituted with 1 or 2 groups selected from ═O, C _3-7 cycloalkyl, hydroxy, amino, dimethylamino, aminocarbonyl, C _1-4 alkoxy or trifluoromethyl. An optionally _substituted C _1-6 alkyl group; R ₉ is hydrogen, C _1-4 alkyl, or R ₉ and R ₈ are selected from oxygen, sulfur and nitrogen together with the nitrogen to which they are attached May contain another heteroatom, C _1-4 alkyl, ═O, S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl or C (O) C _1-4 A 5 may be substituted by 1 or 2 groups selected from the kill to 7-membered heterocyclic group; R ₁₀ and R ₁₁ are independently hydrogen or a C _1-4 alkyl group; X is nitrogen An atom and Y is CH or X is CH and Y is nitrogen; m is 0 or an integer from 1 to 3; n is an integer from 1 to 3; p is 0, 1 or Or a pharmaceutically acceptable salt and solvate thereof; its preparation and its use in the treatment of tachykinin-mediated symptoms.
[Chemical 1]

Description

Detailed Description of the Invention

(Technical field)
The present invention relates to a piperidine derivative, a production method thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.
In particular, the present invention relates to novel compounds that are potent and specific antagonists of tachykinin, including substance P and other neurokinins.

(Conventional technology)
WO 99/37304 discloses, among other things, some 2-aryl-1,4-disubstituted piperidine derivatives as factor Xa inhibitors. Such compounds are useful as blood coagulation inhibitors for mammalian species.
WO 97/16440 and WO 02/32867 disclose certain 2-aryl-1,4-disubstituted piperidines as NK ₁ antagonists.
However, the above publications do not disclose or suggest any of the compounds claimed in this application.

（Ｉ） (Disclosure of the Invention)
Thus, the present invention provides compounds of formula (I):

(I)

[Where:
R is halogen or C _1-4 alkyl;
R ₁ is hydrogen or C _1-4 alkyl;
R ₂ is hydrogen, C _1-4 alkyl, or R ₂ together with R ₃ represents C _3-7 cycloalkyl;
R ₃ is hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-6 alkenyl; or R ₁ and R ₃ together with the nitrogen and carbon atoms to which they are attached respectively, Represents a 6-membered heterocyclic group;
R ₄ is trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethoxy or halogen;
R ₅ is hydrogen and R ₆ is NR ₇ R ₈ or R ₅ is NR ₈ R ₉ and R ₆ is hydrogen;
R ₇ is hydrogen or C _1-4 alkyl, or R ₇ and R ₈ together with the nitrogen to which they are attached are oxygen-containing saturated 5- to 7-membered heterocyclic groups;

R ₈ contains 1 to 3 heteroatoms selected from hydrogen, phenyl, C _3-7 cycloalkyl, (CH ₂ ) _p C (O) NR ₁₀ R ₁₁ , oxygen, sulfur and nitrogen, and C _{1 -4} alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl is selected from saturated 5- to 7-membered heterocyclic groups, oxygen, sulfur and nitrogen 5-membered heteroaryl groups containing 1 to 3 heteroatoms and optionally substituted with C _1-4 alkyl S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl Or R ₈ contains 1 to 3 nitrogen atoms and is substituted with C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl. Or a 6-membered heteroaryl group; R ₈ is fluorine, phenyl _{(optionally, C 1-4} alkyl, optionally substituted with C _{(O) C 1-4} alkyl or halogen), = _{O, C 3-7} cycloalkyl, hydroxy, amino, A C _1-6 alkyl group optionally substituted by 1 or 2 groups selected from dimethylamino, aminocarbonyl, C _1-4 alkoxy or trifluoromethyl;

R ₉ is hydrogen, C _1-4 alkyl, or R ₉ and R ₈ together with the nitrogen to which they are attached contain another heteroatom selected from oxygen, sulfur and nitrogen. _{1 selected} from C _1-4 alkyl, ═O, S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl or C (O) C _1-4 alkyl. Or a 5- to 7-membered heterocyclic group optionally substituted by 2 groups;
R ₁₀ and R ₁₁ are independently hydrogen or a C _1-4 alkyl group;
X is a nitrogen atom and Y is CH or X is CH and Y is nitrogen;
m is 0 or an integer from 1 to 3;
n is an integer from 1 to 3;
p is 0, 1 or 2]
Or a pharmaceutically acceptable salt and solvate thereof.

Suitable pharmaceutically acceptable salts of the compounds of general formula (I) are acid addition salts formed with pharmaceutically acceptable organic or inorganic acids such as hydrochlorides, hydrobromides, sulfates, alkyls. -Or aryl sulfonate (eg methane sulfonate or p-toluene sulfonate), phosphate, acetate, citrate, succinate, tartrate, trifluoroacetate, lactate, fumaric acid Includes salts, malates and maleates.
Solvates are, for example, hydrates.
Hereinafter, the compound according to the present invention includes both the compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable solvate thereof.
Suitable pharmaceutically acceptable salts of the compounds of general formula (I) can be obtained in crystalline form and / or in amorphous form or as a mixture thereof.

One skilled in the art will appreciate that compounds of formula (I) contain at least two chiral centers (ie, carbon atoms designated by * in 1a to 4h).
Thus, when X is CH, Y is nitrogen, R ₅ is hydrogen and R ₆ is NR ₇ R ₈ , the chiral center is represented by formulas (1a, 1b, 1c and 1d). obtain.

When Y is CH, X is nitrogen, R ₆ is hydrogen and R ₅ is NR ₇ R ₈ , the chiral center can be represented by the formulas (2a, 2b, 2c and 2d) it can.

When Y is CH, X is nitrogen, R ₅ is hydrogen and R ₆ is NR ₇ R ₈ , the chiral center can be represented by formulas (3a, 3b, 3c and 3d).

When Y is nitrogen, X is CH, R ₅ is NR ₇ R ₈ and R ₆ is hydrogen, the chiral center is shown in formulas (4a, 4b, 4c and 4d).

A wedge-shaped bond indicates that the bond is above the plane of the paper, which corresponds to the β configuration. The dashed bond indicates that the bond is below the plane of the paper, which corresponds to the α configuration.
In the specific compounds described below in which Y is CH and X is nitrogen, the β configuration at the 2-position of the piperidine ring corresponds to the S configuration, and the β configuration at the 4-position of the piperidine ring is in the R configuration. Equivalent to. The α configuration at the 2-position of the piperidine ring corresponds to the R configuration, and the α configuration at the 4-position of the piperidine ring corresponds to the S configuration.
In the specific compounds described below in which Y is nitrogen and X is CH, the β configuration at the 2-position of the piperidine ring corresponds to the R configuration, and the β configuration at the 4-position of the piperidine ring is the S configuration. Equivalent to. The α configuration at the 2-position of the piperidine ring corresponds to the S configuration, and the α configuration at the 4-position of the piperidine ring corresponds to the R configuration.

The arrangement of the chiral carbon atoms of the piperidine ring shown in 1a, 1c, 2b, 2c, 3b, 3c, 4b and 4c is hereinafter referred to as the anti-configuration, and 1b, 1d, 2a, 2d, 3a, 3d, 4a and 4d is called thin arrangement.
Assignment to the R or S configuration at the 2 and 4 positions was made according to the rules of Cahn, Ingold and Prelog, Experientia 1956, 12, 81.

There may also be additional asymmetric carbon atoms in the compounds of formula (I). If R ₂ and R ₃ are not the same group, the compound of formula (I) has at least 3 asymmetric carbon atoms.
All stereoisomers, including all enantiomers, diastereomers and all mixtures thereof (including racemates) are included within the scope of the invention, and references to compounds of formula (I) are intended unless otherwise indicated. It should be understood that it covers all stereoisomers.
Furthermore, the crystalline form of the compound of formula (I) may exist as polymorphs, which are also included in the present invention.

The term “C _1-4 alkyl” as used herein as a group or part of a group refers to a straight or branched alkyl group having 1 to 4 carbon atoms; Examples of groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, dimethylpropyl, 1-methylethyl or 2-methylpropyl.
The term “C _1-6 alkyl” refers to C _1-4 alkyl and higher thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl or dimethylpropyl. The homologues are included.
The term “C _3-6 alkenyl group” refers to a straight or branched alkenyl group containing 3 to 6 carbon atoms; such groups include, for example, 2-propenyl, 1-propenyl, isopropenyl, 2-butenyl, 2-pentenyl, 2-hexenyl and the like can be mentioned.

When R ₁ and R ₃ together with the nitrogen and carbon atoms to which they are attached each represent a 5- to 6-membered heterocyclic group, this group is saturated or contains a single double bond . This may be a 3,6-dihydro-2H-pyridin-1-yl, piperidin-1-yl or pyrrolidin-1-yl group.
When R ₅ is a 5 or 6 membered heteroaryl group according to the present invention, it includes furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl.
Where R ₇ and R ₈ together with their attached nitrogen represent a 5- to 7-membered heterocyclic group containing oxygen, this group is morpholinyl (eg morpholino), homomorpholinyl, 1,3-oxazolidinyl There may be.
When R ₉ and R ₈ together with the nitrogen to which they are attached are 5- to 7-membered heterocyclic groups optionally containing another heteroatom selected from oxygen, sulfur and nitrogen This group includes piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, imidazolidinyl, pyrrolidinyl and the like.

When R ₈ is a saturated 5- to 7-membered heterocyclic group of the present invention, it includes piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, imidazolidinyl or pyrrolidinyl, 1.3-dioxolanyl and the like.
The term “C _3-7 cycloalkyl group” means a non-aromatic monocyclic hydrocarbon ring having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term “halogen” refers to a fluorine, chlorine, bromine or iodine atom.
The term “C _1-4 alkoxy group” may be a linear or branched alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2. -Oxy.

A preferred group of compounds of the present invention is that R ₆ is NR ₇ R ₈ , R ₅ is hydrogen, Y is nitrogen, X is CH, or R ₆ is hydrogen and R ₅ is NR ₈ R ₉ is a compound in which Y is CH and X is nitrogen. These compounds are each represented by formulas (1) and (2) (wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , m and n are the compounds of formula (I) As defined above).

When Y is nitrogen and X is CH, a preferred group of compounds of formula (I) are those in which the carbon atom at the 2-position of the piperidine ring is in the β-configuration.
A preferred group of compounds of formula (I) are those in the syn configuration.
R is preferably a halogen (eg fluorine) and / or C _1-4 alkyl (eg methyl) group and m is preferably 0 or an integer from 1 to 2.
R ₁ is preferably a methyl group.
R ₂ is preferably a hydrogen atom or a methyl group.
R ₃ is preferably a hydrogen atom or a methyl group.
R ₄ is preferably a trifluoromethyl group and / or halogen (ie chlorine), and n is preferably 2.

R ₅ is preferably hydrogen, NH (C _3-7 cycloalkyl), NH (C _{1-4 alkylC 3-7} cycloalkyl), 1-piperazinyl (optionally C _1-4 alkyl, ═O, Optionally substituted with one or two groups selected from S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl or C (O) C _1-4 alkyl) Piperidyl (optionally C _1-4 alkyl, optionally substituted with one or two groups selected from ═O) or morpholino;
R ₆ is preferably hydrogen, N (C _1-6 alkyl) ₂ , NH (C _1-6 alkyl), NH (CH ₂ ) _p C (O) NR ₁₀ R ₁₁ (where p is 1 or 2 and R ₉ and R ₁₀ are independently hydrogen or methyl), NH (C _1-6 alkyl trifluoromethyl), NH (C _1-6 alkyl C _1-4 alkoxy), NH ( C _1-6 Arukirufu' element), _{N (C 1-6 alkyl) (C 1-6} Arukirufu' element), NH _{(C 1-6} alkyl phenyl), NH _{(C 3-7} cycloalkyl), NH (piperidyl), NH (C _1-6 alkylaminocarbonyl), NH (C _1-6 alkyl-1.3 dioxolanyl) or morpholino.
R ₇ is preferably a hydrogen atom or a methyl group.

R ₈ is preferably hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, CH ₂ C (O) NH ₂ , C _1-6 alkyltrifluoromethyl, C _1-6 alkyl C _1-4 alkoxy. , _{C 1-6} Arukirufu' _{containing, C 1-6} alkyl phenyl, _{piperidyl, C 1-6 alkylaminocarbonyl, C 1-6} alkyl-1,3-dioxolanyl.
R ₉ is preferably a hydrogen atom or a methyl group.
R ₁₀ is preferably a hydrogen atom or a methyl group.
R ₁₁ is preferably a hydrogen atom or a methyl group.
Preferred series of compounds of formula (I) are those wherein R is each independently a halogen (eg fluorine) or C _1-4 alkyl (eg methyl) group and m is 0, 1 or 2. It is. More preferably, m is 1 or 2. Within this range, it is particularly preferred that R is in the 2 and / or 4 position of the phenyl ring.
The compounds of formula (I) (where n is 2) are a preferred series of compounds within which the R ₄ group is preferably in the 3 and 5 positions of the phenyl ring.

Further preferred compounds of formula (I) are
R ₆ is NR ₇ R ₈ , R ₅ is hydrogen, Y is nitrogen and X is CH, or R ₆ is hydrogen, R ₅ is NR ₈ R ₉ , Y Is CH and X is nitrogen;
R ₇ is hydrogen or methyl;
R ₈ is methyl, ethyl, dimethylpropyl, cyclopropyl, cyclobutyl, CH ₂ C (O) NH ₂ , piperidinyl, 1-methyl-piperidinyl, or phenyl, cyclopropyl, 4-acetyl-piperazino, fluorine, methoxy, trifluoro Methyl substituted with a group selected from methyl and 1.3-dioxolanyl;
R ₉ is hydrogen or methyl;
R ₉ and R ₈ together with their bound nitrogen are 1-piperazinyl, acetyl-1-piperazinyl, morpholino;
R ₇ and R ₈ together with their bound nitrogen are morpholinos;
R is independently fluorine or methyl;
R ₄ is trifluoromethyl and / or chlorine;
m is 1 or 2;
n is 2,
It is a thing.

Preferred compounds of the invention are:
4- (2,2-Dimethyl-propylamino) -2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide;
4-Ethylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide ;
4-Dimethylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide ;
4-dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4- (2-Fluoroethyl) -amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis) -trifluoromethyl- Phenyl) -ethyl] -methylamide;
4- (2-fluoro-ethylamino) -2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4- (N-2-fluoroethyl-N-methylamino) -2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)- Methylamide;
2- (4-Fluoro-2-methyl-phenyl) -4- (2-methoxyethylamino) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -Ethyl] -methylamide;
2- (4-Fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide ;
2- (4-Fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;

2- (4-fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4-amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4-Cyclobutylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis) -trifluoromethyl-phenyl) -ethyl] -Methylamide;
4-Cyclopropylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl]- Methylamide;
2- (4-Fluoro-2-methyl-phenyl) -4- [methyl- (1-methyl-piperidin-4-yl) -amino] -piperidine-1-carboxylic acid [1- (R)-(3, 5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide;
4-benzylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4-[(1,3-Dioxolan-2-yl) -methyl] -amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl -Benzyl) -methylamide;
4-(-N-2-fluoroethyl-N-methylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoro Methyl-benzyl) -methylamide;
4- (carbamoylmethyl-amino) -2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
2- (4-fluoro-2-methyl-phenyl) -4-morpholino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;

2- (4-fluoro-2-methyl-phenyl) -4-morpholino-piperidine-1-carboxylic acid 1-[(R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide;
2- (4-fluoro-2-methyl-phenyl) -4-morpholino-piperidine-1-carboxylic acid 1-[(S)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide;
4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide;
4- (4-acetyl-piperazin-1-yl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide;
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide ;
4-cyclopropylmethylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide;
1- (4-fluoro-2-methyl-phenyl) -4-morpholino-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide;
4- (4-acetylpiperazinyl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide; Stereomers and pharmaceutically acceptable salts.

Particularly preferred compounds of the invention are:
4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride;
4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride ;
4- (S)-(2-Fluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3.5 -Bis) -trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride;
4- (S)-(2-Fluoro-ethylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl- Benzyl) -methylamide hydrochloride;
4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride;
4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride ;
4- (S)-(2-Fluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3.5 -Bis) -trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride;
4- (S)-(2-Fluoro-ethylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl- (Benzyl) -methylamide hydrochloride.

The compounds of the present invention are antagonists of tachykinins, including substance P and other neurokinins, both in vitro and in vivo, and thus useful in the treatment of tachykinin-mediated conditions, including substance P and other neurokinins. It is.
The compounds of the present invention also have activity as serotonin reuptake inhibitors.
Tachykinins are a family of peptides having a common carboxyl-terminal sequence (Phe-X-Gly-Leu -Met-NH 2). They are actively involved in the pathology of both lower and higher organisms. The main tachykinins in mammals are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), which act as neurotransmitters and neuromodulators. Mammalian tachykinins may be involved in the pathophysiology of many human diseases.
Three types of tachykinin receptors have been identified, NK ₁ (SP-preferred), NK ₂ (NKA-preferred) and NK ₃ (NKB-preferred), which are central nervous (CNS) and peripheral Widely distributed in the nervous system.
In particular, the compounds of the present invention are antagonists of the NK ₁ receptor.

Based on their efficacy as tachykinin receptor (especially NK ₁ receptor) antagonists, the compounds of the invention are useful in the treatment of CNS disorders and mental disorders, in particular in the treatment or prevention of depression and / or in the treatment of anxiety. It is particularly useful.
Compounds that eliminate and replace [ ³ H] -Substance P (SP) from recombinant human NK ₁ receptor expressed in Chinese hamster ovary (CHO) cell membranes and from cerebral cortex homogenates of gerbils and marmoset NK ₁ -receptor binding affinity was determined in vitro by measuring the ability of
Membrane preparation from hNK ₁ -CHO cells was performed essentially as described by Beattie et al. (Br. J. Pharmacol, 116: 3149-3157, 1995).

hNK ₁ -CHO cells were placed in phosphate buffered saline (PBS) formulated with 5 mM EDTA and centrifuged at 913 g for 8 minutes at 4 ° C. The cells were then placed in 10 volumes of membrane preparation buffer (HEPES 50 mM, pH 7.4 containing 0.1 mM leupeptin, 40 μg / ml bacitracin, 1 mM EDTA, 1 mM Pefabloc and 2 μM pepstatin A). And resuspended to make it homogeneous. The suspension was centrifuged at 48000g for 20 minutes at 4 ° C. The final pellet was again suspended in 10 volumes of membrane preparation buffer and homogenized again. The membrane suspension was then frozen at −80 ° C. until needed.

A 200 μl assay volume consists of test compound (1 pM to 1 μM final concentration), 100 μl [ ³ H] -SP (0.5 nM final concentration) and 100 μl membrane suspension in 2 μl DMSO or increasing concentrations of DMSO. Suspension (8 μg protein per well) is formulated in incubation buffer (50 mM HEPES, pH 7.4, 3 mM MnCl ₂ and 0.02% BSA). Incubation was carried out for 40 minutes at room temperature. Nonspecific binding was identified by adding chilled SP (1 μM). The reaction was stopped by rapid filtration. The filter paper was washed 5 times with 200 μl ice-cold 0.9% w / v NaCl, and the radioactivity was counted in a microplate scintillation counter. In each experiment, the displacer was tested twice at every concentration.

A cerebral cortex homogenate of a gerbil (60 g, Charles River) and a standard marmoset (Callithrix jacchus, 300-400 g, GSK colony, Verona, Italy) was prepared as follows: Weighed, crushed and homogenized with 10 volumes of membrane preparation buffer.
The homogenate was then centrifuged at 48000 g for 20 minutes, and the pellet was washed again by resuspending in 10 volumes of membrane preparation buffer and centrifuged at 48000 g for 20 minutes. The final pellet was resuspended in 7-10 volumes of membrane preparation buffer, subdivided into aliquots and frozen at −80 ° C. until use.
An assay volume of 400 μl requires 100 μl of incubation buffer (50 mM HEPES, pH 7.4, 3 mM MnCl ₂ , and 0.02% BSA) and increasing concentrations of test compound (4 μl DMSO or DMSO). 1 pM-1 μM final concentration), [ ³ H] -SP (0.5 nM-0.8 nM final concentration) in 100 μl incubation buffer, 2 μg / ml leupeptin, 2 μg / ml bacitracin and 0. Consists of a membrane suspension (0.6 mg protein for gerbils and 0.8 mg protein for marmoset) in 200 μl incubation buffer containing 5 μM phosphoramidon. Incubation was performed for 60 minutes at room temperature. Nonspecific binding was identified by adding chilled SP (1 μM). The reaction was stopped by rapid filtration. The filter paper was washed 3 times with 1 ml ice cold wash buffer (containing 50 mM HEPES, pH 7.4 and 3 mM MnCl ₂ ) and radioactivity was counted in a liquid scintillation counter.

The potential of the test compounds to inhibit SP or GR73632-induced increase in [Ca ²⁺ ] ⁱ in hNK ₁ / CHO cells was measured in functional experiments using the FLIPR (fluorimetric imaging plate reader) technique.
hNK ₁ / CHO cells are seeded to a density of 60000 cells per well in Ham F-12 medium supplemented with 10% (v / v) heat-inactivated fetal calf serum and 2 mM glutamine. Cultured overnight. Next, in order to label the cells, 5% CO ₂ in a medium containing fluorescent calcium indicator fluo-4AM (2 μM), organic anion migration inhibitors probenecid (5 mM) and HEPES (20 mM). Incubate for 30 minutes in a humid atmosphere. After washing with Hank's balanced salt solution (HBSS) containing 20 mM HEPES and 2.5 mM probenecid, the cells were washed in a wash buffer containing 0.02% BSA in the absence of the test compound (control) or formulated. Incubated for 60 minutes at 37 ° C. The plates were then placed in the FLIPR and cell fluorescence (ex = 488 nm, em = 510-570 nm) was monitored before and after adding various concentrations of SP or GR73732 in assay buffer. The experiment was performed with the laser set at 1.0 W and using a charge coupled device (CCD) camera shutter speed of 0.4 seconds.
The compounds of the present invention have also been found to show anxiolytic effects in routine tests, such as the Marmoset-Human Threat Test (Costall et al., 1988).

The ability of a compound to drive [ ³ H] -imipramine from human serotonin transporter expressed in human embryonic kidney HEK293 cell membrane (Receptor Biology, Inc.) allows human serotonin transporter (hSERT) binding affinity in vitro. It was measured. For the binding reaction, 4 nM [ ³ H] -imipramine (703 GBq / mmol, Amersham), together with 0.02 mg / ml cell membrane and different concentrations (7 concentrations) of the compound to be tested, 50 mM Tris HCl, Incubated in pH 7.5, 120 mM NaCl and 5 mM KCl. The reaction was performed at 4 ° C. for 60 minutes and was terminated by filtration through a GF / B ultrafiltration 96 well / case (previously soaked in 0.5% PEI) using a cell harvester (Packard). Scintillation liquid was added to each filtered spot, and radioactivity was measured using a scintillation counter (Top Count (Packard)). Nonspecific binding was measured using imipramine (100 μM) and the nonspecific binding was approximately 5% of total binding.
A competition experiment was performed in which each point was measured twice. Competitive binding data was examined using the Msat601 software package.
IC ₅₀ values were converted to K _i values using the Cheng-Prusoff equation.

The inhibitory activity of the compound on the rat serotonin transporter was measured in vitro using rSERT-LLCPK cells (LLCPK cells transfected with rat SERT). Cells were placed on 96-well plates (60000 cells / well). After 24 hours, cells were washed with absorption buffer (Hank balanced salt solution + 20 mM Hepes) and preincubated with 50 μl buffer containing test compound for 10 minutes at room temperature. 50 μl of 50 nM [ ³ H] serotonin (5HT) solution (final concentration: 25 nM [ ³ H] 5HT) is added and the plate is incubated at room temperature for 7 minutes, during which time the cells ingest radiolabeled 5HT. . The solution was aspirated and the cells were quickly washed with cold buffer to finish the uptake.
The amount of radioactive 5HT incorporated into the cells was then measured by adding a scintillation cocktail directly to the cells, and the plate was read on top count. The data was digitally processed to obtain antagonist pIV50 values. PKi values were calculated using the Cheng-Prusoff equation.

The action of the compounds of the present invention at the NK ₁ receptor can be measured using conventional test methods. Therefore, the ability to penetrate the central nervous system and bind to the NK ₁ receptor was determined according to the gerbil foot tapping experiment described in Rupniak & Williams, Eur. J. of Pharmacol., 265, 179-183, 1994. It was revealed in vivo by its inhibitory effect on behavioral changes induced by applying substance P into the ventricle.

The compounds of the present invention treat CNS disorders and psychosis, in particular, treatment of depression as defined in Diagnostic Statistical of mental disorder (DSM) IV edition edit by American Psychiatric association and international classification Diseases 10th revision (ICD10) Useful for, but not limited to, prevention and / or treatment of anxiety.
Thus, for example, depression includes bipolar depression, unipolar depression, single or recurrent major depressive episodes, major depressive disorder (MDD), including recurrent major depression, which includes anorexia, It may or may not be accompanied by psychotic features, tension features, depressive features, including weight loss, atypical features, anxiety depression, circulatory disease or postpartum onset.

Other mood disorders within the term major depression include premature or late-onset mood disorders with or without atypical features, neurological depression, post-traumatic stress disorder and social fear Alzheimer's dementia with early or late, depressed mood; Vascular dementia with depressed mood; Alcohol, amphetamine, cocaine, halsinogen, inhalation, opioid, phencyclidine, sedative, Includes mood disorders induced by hypnotics, anxiolytics and other substances; depression-type schizophrenic emotional disorders; and adaptation disorders with depressed mood. Major depressive disorder can also result from general medical conditions such as, but not limited to, myocardial infarction, diabetes, and miscarriage.
The term “anxiety” refers to panic disorder with or without agoraphobia, agoraphobia such as interpersonal or agoraphobia, obsessive-compulsive disorder, stress disorders including posttraumatic stress disorder, generalized Includes sexual anxiety disorder, acute stress disorder and anxiety-depressed disorder.

  The compounds of the present invention are useful as analgesics. In particular, they are traumatic pain such as postoperative pain; traumatic exfoliation pain such as brachial plexus; chronic pain such as arthritic pain as occurs in osteoarthritis, rheumatoid arthritis or psoriatic arthritis; , Neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, knee neuralgia, glossopharyngeal neuralgia, sympathy Neuropathic dystrophy, neuropathic pain such as limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporal mandibular pain, maxillary sinus pain, cluster headache; toothache; Cancer pain; internal organ pain; gastrointestinal pain; nerve entrapment pain; sports trauma pain; Meningitis, arachnoiditis, musculoskeletal pain; lower back pain, eg spinal stenosis; disc sag; sciatica; angina; ankylosing spondylitis; gout; burns; scar pain; As well as useful for the treatment of thalamic pain, such as post-stroke thalamic pain.

The compounds of the present invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, sleep seizures and circadian rhythm disorders.
The compounds of the present invention are also useful in the treatment or prevention of cognitive impairment. Cognitive impairment includes dementia, forgetfulness and other cognitive impairments.
Moreover, the compounds of the present invention are also useful as enhancers of memory and / or cognition in healthy individuals without cognitive and / or memory deficiencies.
The compounds of the present invention are also useful in the treatment of tolerance and dependence on many substances. For example, they treat addiction to nicotine, alcohol, caffeine, phencyclidine (phencyclidine-like compounds), or treat opiates (eg cannabis, heroin, morphine) or tolerance and addiction to benzodiazepines; It is also useful in the treatment of cocaine, sedative ipnotic, amphetamine or amphetamine related drugs (eg, dextroamphetamine, methylamphetamine) or their complications.

The compounds of the present invention are also useful as anti-inflammatory agents. In particular, they are induced by inflammation of asthma, influenza, chronic bronchitis and rheumatoid arthritis; gastrointestinal inflammatory diseases such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drugs Useful in the treatment of inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation.
The compounds of the present invention are also useful in the treatment of allergic disorders, in particular skin allergic disorders such as urticaria, and airway allergic disorders such as rhinitis.
The compounds of the present invention are also useful for the treatment or prevention of delusional schizophrenia, disorganized schizophrenia, tonic schizophrenia, atypical schizophrenia, residual schizophrenia.

  The compounds of the present invention are also useful in the treatment of vomiting, ie nausea, nausea and nausea. Vomiting includes acute vomiting, delayed vomiting, and prior vomiting. However, the compounds of the present invention are also useful for the treatment of induced vomiting. For example, vomiting is an alkylating agent such as cancer chemotherapeutic agents such as cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics such as dactinomycin, doxorubicin, mitomycin-C and bleomycin; Induced by drugs such as metabolites such as cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids such as etoposide, vinblastine and vincristine; and other substances such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof Discomfort due to radiation; radiation therapy, e.g. irradiation to the chest or abdomen as in the treatment of cancer; poisons; metabolic diseases or infections, e.g. due to gastritis Toxins such as toxins that are elicited or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders such as motion sickness, dizziness, depression, and Meniel's disease; postoperative discomfort; Gastrointestinal closure; decreased gastrointestinal motility; visceral pain such as myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (eg, altitude sickness); opioid analgesics such as morphine; Triggered by gastric-esophageal reflux disease (GERD) such as GERD and symptomatic GERD or non-erosive GERD, hyperacidity, dysphagia, acid stomach, sour stomach, heartburn / reflux, episodic heartburn, nighttime heartburn and diet It may be induced by heartburn, such as heartburn, dyspepsia and functional dyspepsia.

The compounds of the present invention may also be used in gastro-esophageal reflux diseases (GERD) such as irritable bowel syndrome, erosive GERD and symptomatic GERD or non-erosive GERD, hyperacidity, binge eating, acid stomach, sour stomach, heartburn / Reflux, episodic heartburn, heartburn such as nocturnal heartburn and heartburn induced by meals, dyspepsia and functional dyspepsia (such as ulcer-like dyspepsia, dyspepsia and unspecified dyspepsia), chronic constipation; Skin diseases such as psoriasis, pruritus and sunburn; vasospasm diseases such as angina, vascular headache and Raynaud's disease; cerebral ischemia such as cerebral vasospasm after subarachnoid hemorrhage; scleroderma and eosinophilic cirrhosis Fibrosis and collagen disease such as symptom; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrosis; Useful in the treatment of cough.
The compounds of the present invention are also useful in premenstrual dysphoric disorder (PMDD), chronic fatigue syndrome and multiple sclerosis.

The compounds of the present invention have been found to exhibit anxiolytic and antidepressant activity in routine tests, such as the test of vocalization induced by separating guinea pig children (Molewik et al., 1996).
The compounds of the present invention are also useful in the treatment of convulsions and epilepsy.
The compounds of the present invention are combined with other active substances such as 5HT3 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants or dopaminergic antidepressants May be administered.
Suitable 5HT3 antagonists that can be used in combination with the compounds of the present invention include, for example, ondansetron, granisetron, and metoclopramide.

Suitable serotonin agonists that can be used in combination with the compounds of the present invention include sumatriptan, lauborsin, yohimbine and metoclopramide.
Suitable SSRIs that can be used in combination with the compounds of the present invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.
Suitable SNRIs that can be used in combination with the compounds of the present invention include venlafaxine and reboxetine.
Suitable tricyclic antidepressants that can be used in combination with the compounds of the present invention include imipramine, amitriptyline, clomipramine and nortriptyline.
Suitable dopaminergic antidepressants that can be used in combination with the compounds of the present invention include bupropion and amineptin.
It will be appreciated that the compounds used in combination can be administered simultaneously (either in the same or separate pharmaceutical formulations) or separately.

The present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, particularly in human therapy.
As a further aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in the treatment of a condition mediated by tachykinin, including substance P and other neurokinins Use of objects is also provided.
In another or further embodiment, a method of treating a mammal, including a human, particularly a method of treating a condition mediated by tachykinin, including substance P and other neurokinins, comprising an effective amount of formula (I) There is provided a method comprising administering a compound or a pharmaceutically acceptable salt thereof.

It will be understood that reference to treatment is intended to include prevention and alleviation of established symptoms. While the compound of formula (I) may be administered as a raw chemical, it is preferred that the active ingredient be provided as a pharmaceutical composition.
Accordingly, the present invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated to be administered by any convenient route. Preferably, such compositions are in a form adapted for use in medicine, particularly human medicine, and are conveniently used with one or more pharmaceutically acceptable carriers or excipients. Can be prescribed in various ways.
Thus, the compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including eye and nose), depot or rectal administration, or by inhalation or infusion (via mouth or nose) It is good also as a form suitable for administration by (1).

  When administered orally, the pharmaceutical composition comprises, for example, a binder (eg, pre-gelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); a filler (eg, lactose, microcrystalline cellulose or calcium hydrogen phosphate); A pharmaceutically acceptable excipient such as a lubricant (eg, magnesium stearate, talc or silica); a disintegrant (eg, potato starch or sodium starch glycolate); or a wetting agent (eg, sodium lauryl sulfate). It may be in the form of tablets or capsules that are used and manufactured by conventional means. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or they may be provided as a dry product that is reconstituted with water or a suitable vehicle prior to use. Suspensions (eg, sorbitol syrup, cellulose derivatives or hydrogenated edible oil); emulsifiers (eg, lecithin or acacia); non-aqueous vehicles (eg, tonsils, oily esters, ethyl alcohol or fractionated vegetable oils); and storage Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as pharmacological agents such as methyl or propyl p-hydroxybenzoate or sorbic acid. The preparation may contain buffer salts, flavoring agents, colorants and sweeteners as appropriate.

Preparations for oral administration are suitably formulated to give controlled release of the active ingredient.
For buccal administration, the composition may be in the form of tablets or lozenges formulated by conventional procedures.
The compounds of the present invention may be formulated for parenteral administration by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, for example, in an ampoule or in a multi-dose container with a preservative. The composition may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulations such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form that is reconstituted with a suitable vehicle, eg, sterile pyrogen-free water, before use.

The compounds of the present invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (eg, eye, ear or nose drops). Ointments and creams may be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized ingredients.
Lotions may be formulated with an aqueous or oily base and will in general contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Drops may be formulated with an aqueous or non-aqueous substrate further comprising one or more dispersants, stabilizers, solubilizers or suspending agents. They may contain preservatives.

The compounds of the present invention may be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.
The compounds of the present invention may be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the invention may be formulated with a suitable polymeric or hydrophobic material (eg, as an acceptable emulsion in an oil) or with an ion exchange resin, or a slightly less soluble derivative, such as You may prescribe it as a salt which is hard to dissolve.

For intranasal administration, the compounds of the invention may be formulated as powder mixtures for administration via suitable metering or unit dose devices, or with suitable carriers for administration using suitable delivery devices. Good.
A suggested dose of the compound of the invention is 1 to about 1000 mg per day. It will be appreciated that doses may need to be routinely varied depending on the patient's age and symptoms, and the exact dose will ultimately be determined by the advisor or veterinarian. The dosage will depend on the route of administration and the individual compound selected.

The compounds of formula (I) and their salts and solvates may be prepared by the following general methods. In the following description, groups R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ or R ₁₁ , m, n and p unless otherwise specified. Has the same meaning as already defined for the compounds of formula (I).

（ＩＩ）
［式中、Ｒ_１２は＝Ｏであり、Ｒ_１３は水素であるか、またはＲ_１２は水素であり、Ｒ_１３は＝Ｏである］
で示される化合物を、式（ＩＩＩ）：
ＮＲ_５Ｒ_６ （ＩＩＩ）
で示されるアミン誘導体またはその塩で還元的Ｎ−アルキル化に付すことで調製される。反応は、一般に、ジクロロエタンなどの非プロトン性溶媒中、ホウ水素化ナトリウムまたはトリアセトキシホウ水素化ナトリウムなどの適当な金属の還元剤の存在下で行われる。 The compound of formula (I) is represented by formula (II):

(II)
[Wherein R ₁₂ is ═O and R ₁₃ is hydrogen, or R ₁₂ is hydrogen and R ₁₃ is ═O]
A compound of formula (III):
NR ₅ R ₆ (III)
It is prepared by subjecting to reductive N-alkylation with an amine derivative represented by The reaction is generally carried out in an aprotic solvent such as dichloroethane in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride.

で示される化合物を、トリホスゲンと、ジクロロメタンなどの非プロトン性溶媒中、トリエチルアミンなどの有機塩基の存在下で反応させて中間体の化合物（Ｖ）

を形成させ、その化合物は必要ならば単離してもよく、つづいて化合物（Ｖ）をアミン化合物（ＶＩ）

と反応させて調製することができる。 In a further embodiment of the invention, the compound of formula (I), wherein X is CH and Y is nitrogen, is a compound of formula (IV):

The intermediate compound (V) is reacted with triphosgene in an aprotic solvent such as dichloromethane in the presence of an organic base such as triethylamine.

And the compound may be isolated if necessary, followed by conversion of compound (V) to amine compound (VI)

It can be prepared by reacting with.

  The reaction is conveniently carried out in an aprotic solvent such as a hydrocarbon, a halohydrocarbon such as dichloromethane or an ether such as tetrahydrofuran, optionally in the presence of a base such as a tertiary amine, for example diisopropylethylamine. .

で示されるカルボン酸の活性化誘導体を、アミン（ＶＩ）またはその塩と、所望により適当な塩基の存在下で反応させることにより調製することができる。 In a further embodiment of the invention, the compound of formula (I), wherein X is nitrogen and Y is CH, is represented by formula (VII):

Can be prepared by reacting with an amine (VI) or a salt thereof in the presence of a suitable base, if desired.

Suitable activated derivatives of the carboxyl group include the corresponding acyl halides, mixed anhydrides, activated esters such as thioesters or coupling agents such as those used in peptide chemistry with carboxylic acid groups such as O- (benzotriazole -1-yl) -N, N, N′N′-tetramethyluronium tetrafluoroborate derivatives are included.
The reaction is preferably carried out in an aprotic solvent such as an ether such as tetrahydrofuran, a hydrocarbon such as dichloromethane, N, N-dimethylformamide or acetonitrile.
Suitable bases for use in this reaction include organic bases such as triethylamine or N, N diisopropylethylamine.

  The activated derivative of carboxylic acid (VII) can be prepared by conventional means. Particularly suitable activated derivatives for use in this reaction are carboxylic acid (II) and O- (benzotriazol-1-yl) -N, N, N′N′-tetramethyluronium tetrafluoroborate, ether For example, tetrahydrofuran, halohydrocarbons such as dichloromethane, amides such as N, N-dimethylformamide or acetonitrile.

［式中：Ｒ_１２およびＲ_１３は式（ＩＩ）の化合物で定義した意義と同じであり、Ｒａは窒素保護基である］
で示される化合物を、窒素保護基Ｒａを除去した後で、式（ＩＶ）の化合物から式（Ｉ）の化合物を調製したのと同じ操作を用いて処理することにより調製することができる。 A compound of formula (II), wherein X is CH and Y is nitrogen, is represented by formula (VIII):

[Wherein R ₁₂ and R ₁₃ are as defined in the compound of formula (II), and Ra is a nitrogen protecting group]
Can be prepared by removing the nitrogen protecting group Ra, followed by treatment using the same procedure for preparing the compound of formula (I) from the compound of formula (IV).

で示される化合物を、式（ＶＩＩ）の化合物から式（ＩＩ）の化合物を調製したのと同じ操作を用いて処理することで調製することができる。 Compounds of formula (II) (R ₁₂ and R ₁₃ are as defined for compounds of formula (II), Y is nitrogen and X is CH) are those of formula (IX):

Can be prepared using the same procedure as the preparation of the compound of formula (II) from the compound of formula (VII).

Compounds of formula (IV) and (VII) can be prepared by reducing piperidine and carboxylic acid (IX) of formula (VIII) or esters thereof (such as methyl, ethyl, etc.) using amine derivatives (III) or salts thereof, respectively. It can be prepared by subjecting to selective N-alkylation. The reaction is conveniently carried out in an aprotic solvent such as dichloroethane in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride.
Compounds of formula (VIII) are known compounds or can be prepared by methods analogous to those used for known compounds.
Thus, for example, compound (VIII) and its enantiomers can be obtained using the Comins reaction described in Journal American Chemical Society 1994, 116, 4719-4728, followed by 2,3-dihydro-1H-pyridin-4-one. Derivatives can be prepared by reducing to piperidin-4-one derivatives. The reduction can be carried out using hydrogen and a metal catalyst such as a suitable support such as carbon or palladium on alumina. The reaction is performed in a solvent such as an ester, for example, ethyl acetate.

Compounds of formula (IX) (R ₁₃ is ═O and R ₉ is hydrogen) are known compounds, which are Bioorganic & Medicinal Chemistry Letters, Volume 2, No. 11, pages 1357-1360, Can be prepared according to the procedure described in 1992.
Compounds of formula (IX) (R ₁₂ is ═O and R ₈ is hydrogen) are novel compounds, which react amine (XIV) with glyoxalic acid to give intermediate (XIII), It can be prepared by converting it to 4-oxo-tetrahydropyridine intermediate (XII), which in turn is reduced to an intermediate of formula (XI).

The compounds of formula (III) are known compounds or can be prepared by methods analogous to those used for known compounds.
If it is desired to isolate the compound of formula (I) as a salt, for example as a pharmaceutically acceptable salt, this means that the compound of formula (I) in free base form is combined with a suitable amount of a suitable acid, It can be achieved by reacting in a suitable solvent such as an alcohol (eg ethanol or methanol), an ester (eg ethyl acetate) or an ether (eg diethyl ether or tetrahydrofuran).
Pharmaceutically acceptable salts may also be prepared using conventional methods from other salts, including other pharmaceutically acceptable salts of the compounds of formula (I).

The compound of the formula (I) can be isolated in a state where solvent molecules are bound by crystallization from an appropriate solvent or by evaporation of an appropriate solvent, and a corresponding solvate can be easily obtained.
If a particular enantiomer of a compound of general formula (I) is required, it can be obtained, for example, by resolution of the corresponding enantiomeric mixture of a compound of formula (I) by conventional procedures.
Thus, for example, a particular enantiomer of a compound of formula (I) can be obtained from the corresponding enantiomeric mixture of a compound of formula (I) using chiral HPLC procedures.

Enantiomers of compounds of general formula (I) can also be synthesized from suitable optically active intermediates using any of the general methods described herein.
Thus, for example, the required enantiomer provides the corresponding chiral piperidin-4-one of formula (IV) using the method described above for the preparation of a compound of formula (I) from compound (VII), It can then be prepared by isolating a diastereomeric mixture of the compound of formula (I) using conventional procedures.
A chiral compound is prepared from the corresponding racemic compound (IV) using conventional procedures such as salt formation with an appropriate optically active acid, and the resulting diastereomeric salts are obtained by conventional means such as chromatography, The diastereomeric salt may be separated by crystallization and subsequently hydrolyzed.
A suitable optically active acid used in the process is L-(+)-mandelic acid.

In a further embodiment of the invention, an enantiomer of a compound of formula (I) is prepared by reaction with chiral amine (VI) using any of the methods described above for preparing a compound of formula (I) from amine (V). May be.
The chiral amine (III) can be prepared from the corresponding racemic amine (III) using any conventional method such as salt formation with a suitable optically active acid.

The present invention is further illustrated by the following intermediates and examples, which do not limit the invention in any way.
In intermediates and examples, unless otherwise noted:
The melting point (mp) was measured with a Buchi melting point measuring apparatus, but it was not corrected. All temperatures refer to 0 ° C.
Infrared spectra were measured with a FT-IR apparatus in chloroform or Nujol solution. Proton nuclear magnetic resonance (NMR) spectra were recorded on a Varian instrument at 400 or 500 MHz, and chemical shifts were given in ppm (δ) using the residual solvent line as an internal standard. The splitting patterns were intended to be singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and wide (b). Mass spectra (MS) were measured with a VG Quattro mass spectrometer. The optical rotation was measured at 20 ° C. with a Jasco DIP360 apparatus (1 = 10 cm, cell volume = 1 mL, λ = 589 nm).

Flash silica gel chromatography was performed on silica gel 230-400 mesh supplied by Merck AG Darmstadt, Germany. Tlc means thin layer chromatography on a 0.25 mm silica gel plate (60F-254 Merck), visualized with UV light.
The solution was dried over anhydrous sodium sulfate.
Methylene chloride was redistilled over calcium hydride and tetrahydrofuran was redistilled over sodium.
The following abbreviations were used in the text: AcOEt = ethyl acetate, CH = cyclohexane, DCM = methylene chloride, DMF = N, N′-dimethylformamide, DIPEA = N, N-isopropylethylamine, Et 2 O = diethyl ether, EtOH = Ethanol, MeOH = methanol, TEA = triethylamine, THF = tetrahydrofuran.

Diastereomer A refers to a mixture of compounds having the anti configuration described above.
Diastereomer B refers to a mixture of compounds having the syn configuration described above.
Diastereomer 1 refers to a single diastereomer whose absolute configuration has not been determined.
Diastereomer 2 refers to a single diastereomer whose absolute configuration has not been determined.

Intermediate 1
1- (Benzyloxycarbonyl) -2- (4-fluoro-2-methyl-phenyl) -2,3-dihydro-4-pyridone Magnesium shavings (13. 2 g) in dry THF (300 mL) was added to the suspension and then the mixture was vigorously refluxed for 20 minutes. To this suspension was added a solution of 15% 2-bromo-5-fluoro-toluene (52.5 mL) in anhydrous THF (300 mL). The suspension was heated with vigorous reflux until the brown color disappeared. The remainder of the bromide solution was added dropwise to the reflux suspension over 1 hour and then stirred for an additional hour. This Grignard reagent solution was added dropwise to the pyridinium salt obtained from benzyl chloroformate (48.7 mL) and 4-methoxypyridine (25 mL) in dry THF (900 mL) at -23 ° C.
The resulting solution was stirred at −20 ° C. for 1 hour, then warmed to 20 ° C., 10% hydrochloric acid solution (560 mL) was added, and the aqueous layer was extracted with AcOEt (2 × 750 mL).
The combined organic extracts were washed with 5% sodium bicarbonate solution (600 mL) and brine (600 mL) and then partially concentrated in vacuo.
CH (400 mL) was added dropwise at 20 ° C. over 1 hour and the resulting mixture was stirred for 30 minutes then filtered to give the title compound as a white solid (66 g).

IR (Nujol): 1726 and 1655 (C = O), 1608 (C = C) cm- ¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.19 (d, 1H); 7.31-7.18 (m, 5H); 7.08 (m, 2H); 6.94 (dt, 1H) ); 5.77 (d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 2.26 (S, 3H).
MS (ES / +): m / z = 340 [MH] ^<+> .

Intermediate 2
2- (4-Fluoro-2-methyl-phenyl) -piperidin-4-one Method A:
2-Fluoro-4-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at room temperature under a nitrogen atmosphere. . After 1 hour, the mixture was heated to reflux for 16 hours and then cooled to room temperature. This solution was slowly added to a refluxing solution of p-toluenesulfonic acid (10.6 g) in dry benzene (50 mL) that was previously refluxed for 1 hour on a Dean-Stark apparatus. After 3.5 hours, the crude solution was cooled, basified with saturated potassium carbonate solution and dissolved in AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3 × 50 mL) and Et 2 O (2 × 50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as a residue (7.23 g). A part (3 g) of the crude mixture was dissolved in 6N hydrochloric acid solution (20 mL) and stirred at 60 ° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5 × 50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.

Method B
L-Selectride (1M solution in dry THF, 210 mL) was added dropwise over 80 minutes to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to −72 ° C. under a nitrogen atmosphere. After 45 minutes, 2% sodium bicarbonate solution (994 mL) was added dropwise and the solution was extracted with AcOEt (3 × 994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacuo to give 1-benzyloxycarbonyl-2- (4-fluoro-2-methyl-phenyl) -piperidin-4-one as a pale yellow thick oil (94 g), It was used as a crude product.
This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd / C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through celite and the organic phase was concentrated in vacuo to give crude 2- (4-fluoro-2-methyl-phenyl) -piperidin-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at room temperature and racemic camphor sulfonic acid (48.3 g) was added. The mixture was stirred at room temperature for 18 hours, then the solid was filtered, washed with AcOEt (2 × 50 mL), dried under vacuum for 18 hours, and 2- (4-fluoro-2-methyl-phenyl) -piperidine-4- On-10-camphorsulfonate was obtained as a pale yellow solid (68.5 g). Melting point: 167-169 ° C; NMR (d ₆ -DMSO): δ (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 ( m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37 (s + d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s , 3H); 0.73 (s, 3H).

This material (68.5 g) was suspended in AcOEt (480 mL) and stirred with saturated sodium bicarbonate solution (274 mL). The organic layer was separated and further washed with water (274 mL). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil.
NMR (d ₆ -DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2. 82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H) ); 2.18 (m, 1H).
MS (ES / +): m / z = 208 [MH] ^<+> .

Intermediate 3
2- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide Triphosgene (1) dissolved in dry DCM (10 mL) A solution of .43 g) was added to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 mL) in dry DCM (20 mL) precooled to 0 ° C. under a nitrogen atmosphere. The solution was stirred at 0 ° C. for 2 hours, then (3,5-bis-trifluoromethyl-benzyl) -methylamine hydrochloride (5.63 g) and DIPEA (3.34 mL) were added. The mixture was stirred at room temperature under nitrogen for 14 hours. The mixture was dissolved in AcOEt (50 mL) and washed with 1N cold hydrochloric acid solution (3 × 20 mL) and brine (10 mL). The organic layer was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / CH 3: 7) to give the title compound (3.85 g) as a white foam.
IR (Nujol): 1721 and 1641 (C = O) cm- ¹ .
NMR (d ₆ -DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H); 3.63-3.49 (m, 2H); 2.79 (S, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2.26 (s, 3H).
MS (ES / +): m / z = 491 [MH] ^<+> .

Intermediate 4
2- (R)-(4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -Methylamide (4a)
And 2- (S)-(4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl ] -Methylamide (4b)

Method A:
A solution of triphosgene (147 mg) in dry DCM (5 mL) was added dropwise under nitrogen to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL) previously cooled to 0 ° C. After 2 hours, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) were added, The mixture was heated at 70 ° C. for 16 hours. Additional [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (100 μL) were added and the mixture was stirred at 70 ° C. for a further 4 hours. did. The mixture was then cooled to room temperature, dissolved in AcOEt (30 mL) and washed with 1N hydrochloric acid cold solution (3 × 15 mL) and brine (2 × 10 mL). The organic layer is dried and concentrated under vacuum to a residue that is purified by flash chromatography (CH / AcOEt 8: 2):
1. Intermediate 4a white foam (230 mg);
2. A white foam (231 mg) of intermediate 4b was obtained.

Intermediate 4a:
NMR (d ₆ -DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H) 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
MS (ES / +): m / z = 505 [MH] ^<+> .

Intermediate 4b:
NMR (d ₆ -DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H) ); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).
MS (ES / +): m / z = 505 [MH] ^<+> .

Intermediate 4a
Method B
A saturated solution of sodium bicarbonate (324 mL) was added to a solution of Intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous layer was back extracted with additional AcOEt (216 mL) and the combined organic extracts were dried and concentrated under vacuum to give Intermediate 8 yellow oil which was treated with TEA (19 mL) and AcOEt (114 mL). . The resulting solution was added dropwise to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0 ° C. over 40 minutes under a nitrogen atmosphere while maintaining the temperature between 0 ° C. and 8 ° C.
After stirring for 1 hour at 0 ° C. and 3 hours at 20 ° C., [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reaction mixture, which was then heated to reflux for 16 hours.
The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4 × 150 mL), water (3 × 180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacuo to a residue that was purified through a silica pad (CH / AcOEt 9: 1) to give the title compound (21.5 g) as a brown thick oil. .
NMR (d ₆ -DMSO): δ (ppm) 7.97-7.77 (bs + bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H) ); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (M, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 5
2- (S)-(4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid [1- (S)-(3,5-bis-trifluoromethyl-phenyl) -ethyl ] -Methylamide (5a) and 2- (R)-(4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid [1- (S)-(3,5-bis-tri Fluoromethyl-phenyl) -ethyl] -methylamide (5b)

A solution of triphosgene (147 mg) in dry DCM (5 mL) was added to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL), precooled to 0 ° C., under a nitrogen atmosphere. After 2 hours, a solution of [1- (S)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (510 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) was added. And the mixture was heated at 70 ° C. for 16 hours. Then additional [1- (S)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (105 μL) were added. After an additional 4 hours at 70 ° C., the mixture was cooled to room temperature, taken up with AcOEt (30 mL) and washed with 1N cold hydrochloric acid solution (3 × 15 mL) and brine (2 × 10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (CH / AcOEt 8: 2),
1. White foam of intermediate 5a (234 mg);
2. A white foam (244 mg) of intermediate 5b was obtained.

Intermediate 5a:
NMR (d ₆ -DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H) 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
MS (ES / +): m / z = 505 [MH] ^<+> .

Intermediate 5b:
NMR (d ₆ -DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H) ); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).
MS (ES / +): m / z = 505 [MH] ^<+> .

Intermediate 6
2- (S)-(4-Fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5 Methyl-cyclohexyl ester (6a)
And 2- (R)-(4-fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (1R, 2S, 5R) -2-isopropyl-5 -Methyl-cyclohexyl ester (6b)

A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) was added to a mixture of magnesium (525 mg) and iodine (1 crystal) in dry THF (5 mL) previously heated to 70 ° C. The solution was added dropwise over 30 minutes under a nitrogen atmosphere. The mixture was stirred at 70 ° C. for 1.5 hours and then cooled to room temperature.
A solution of menthyl (-)-menthyl chloroformate (3.53 mL) in dry THF (15 mL) was precooled to -78 ° C. with a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL) under a nitrogen atmosphere. Added below. After 15 minutes, a solution containing 4-fluoro-2-methyl-phenylmagnesium bromide was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 mL), warmed to room temperature and stirred at 23 ° C. for 30 minutes. After extraction with AcOEt (2 × 150 mL), the combined organic extracts were washed with brine (50 mL), dried and concentrated under vacuum to a residue that was flash chromatographed (CH / THF / toluene 8: 1). 1) and purified
1. Intermediate 6a (3.44 g-yellow oil)
2. Intermediate 6b (530 mg-white solid) was obtained.

Intermediate 6a:
t. l. c: cyclohexane / THF / toluene 7: 2: 1, Rf = 0.59.
IR (Nujol): 1718 and 1675 (C = O) cm- ¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95 (m, 1H); 68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.7 (m, 4H) ); 1.33 (m, 2H); 0.8 (m, 11H).
MS (ES / +): m / z = 388 [MH] ^<+> .

Intermediate 6b:
Melting point: 117-120 ° C
t. l. c. : Cyclohexane / THF / toluene 7: 2: 1, Rf = 0.56.
IR (Nujol): 1718 and 1669 (C = O) cm- ¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H); 5.35 (d, 1H) 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m, 3H); 1.2-0.7 ( m, 8H); 0.51-0.34 (bs, 6H)
MS (ES / +): m / z = 388 [MH] ^<+> .

Intermediate 7
2- (R)-(4-Fluoro-2-methyl-phenyl) -2,3-dihydro-1H-pyridin-4-one sodium methoxide (100 mg) was added to intermediate 6b (170 mg) under nitrogen atmosphere. To the solution in MeOH (15 mL). The mixture was refluxed for 2 hours and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated and the aqueous phase was extracted with additional AcOEt (4 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.
NMR (d ₆ -DMSO): δ (ppm) 7.71 (bd, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03 (m, 2H); 86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.31 (m, 4H)
MS (ES / +): m / z = 206 [M + H] ^< +>.

Intermediate 8
2- (R)-(4-Fluoro-2-methyl-phenyl) -piperidin-4-one Palladium on activated carbon (10% -74 mg) in intermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). Added to the solution. The mixture was reacted with hydrogen overnight in a pressurized reactor (2 atm). After flushing with nitrogen, the solution was filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the title compound (26 mg) as a yellow oil.
Enantiomeric excess (90-95%) was detected by chiral HPLC.
t. l. c. : AcOEt / MeOH 9: 1, Rf = 0.2.
NMR (d ₆ -DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2. 82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H) ); 2.18 (m, 1H).
MS (ES / +): m / z = 208 [MH] ^<+> .

Intermediate 9
2- (R)-(4-Fluoro-2-methyl-phenyl) -piperidin-4-one L-(+)-mandelate L-(+)-Mandelic acid (22.6 g) in AcOEt (308 mL) Was added to a solution of Intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated to 274 mL under vacuum. The solution was cooled to 0 ° C. and further cold isopropanol (96 mL) was added. The thick precipitate was stirred at 0 ° C. under nitrogen for 5 hours, then filtered and washed with cold Et 2 O (250 mL) to give the title compound as a pale yellow solid (20.3 g).
Melting point: 82-85 ° C.
NMR (d ₆ -DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (M, 4H); 2.29 (s, 3H).
Chiral HPLC: HP 1100 HPLC system; column chiral cell OD-H, 25 cm × 4.6 mm; mobile phase: n-hexane / isopropanol 95: 5 + 1% diethylamine; flow rate = 1.3 ml / min; λ = 240/215 nm; retention Time: 12.07 minutes.

Intermediate 10
2- (R) -4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide Method A
A solution of triphosgene (17 mg) in dry DCM (2 mL) was added to a solution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 mL), precooled to 0 ° C., under a nitrogen atmosphere. After 2 hours, acetonitrile (10 mL) was added to bring the temperature to room temperature, nitrogen was flushed and DCM was evaporated. A solution of 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (74 mg) and DIPEA (130 mg) in acetonitrile (3 mL) was then added and the mixture was stirred at 23 ° C. overnight. The solvent was concentrated under vacuum. The residue was dissolved in AcOEt (10 mL) and washed with 1N hydrochloric acid solution (3 × 5 mL), 5% sodium bicarbonate (5 mL) and brine (10 mL). The organic layer was dried and concentrated in vacuo to a residue that was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (50 mg) as a white solid.

Method B
A saturated solution of sodium bicarbonate (348 mL) was added to a solution of intermediate 9 (23.2 g) in AcOEt (348 mL) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous layer was back extracted with additional AcOEt (230 mL) and the combined organic extracts were dried and concentrated in vacuo to give Intermediate 8 (12.31 g) as a yellow oil, which was TEA (20.5 mL). And treated with AcOEt (123 mL). The resulting solution was added dropwise to a solution of triphosgene (8 g) in AcOEt (61 mL) previously cooled to 0 ° C. over 40 minutes under a nitrogen atmosphere while maintaining the temperature between 0 ° C. and 8 ° C.
After stirring at 20 ° C. for 2 hours, 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (28.1 g), AcOEt (184 mL) and TEA (33 mL) were added to the reaction mixture, and then The mixture was stirred at 20 ° C. for a further 2 hours.
This solution was washed with 10% sodium hydroxide solution (3 × 185 mL) and 1% hydrochloric acid solution (3 × 185 mL). The organic layer was dried and concentrated under vacuum to the crude (38 g) which was purified through a silica pad (CH / AcOEt, 9: 1 to 1: 1) and the title compound (24.7 g) Was obtained as a colorless oil.
NMR (d ₆ -DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98 (dd, 1H); 90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60 (m, 2H); 2.69 (m, 2H) 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s, 3H).
MS (ES / +): m / z = 491 [MH] ^<+> .

Intermediate 11
2- (4-Fluoro-2-methyl-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide Intermediate 3 (150 mg) and sodium borohydride A solution of (13 mg) in dry MeOH (5 mL) was stirred at 0 ° C. for 2 hours under a nitrogen atmosphere. The crude solution was washed with saturated ammonium chloride solution (4 mL) and dissolved with AcOEt (5 mL). The aqueous phase was extracted with AcOEt (3 × 5 mL) and the combined organic phases were washed with brine (5 mL). The organic layer is dried and concentrated under vacuum to a residue, which is subjected to flash chromatography (AcOEt / CH 7: 3):
1. Intermediate 11a (4 mg)
2. Intermediate 11b (30 mg) was obtained.

Intermediate 11a (Diastereomer A)
NMR (d ₆ -DMSO): δ (ppm) 7.94 (bs, 1H); 7.63 (bs, 2H); 7.22 (bs, 1H); 6.88 (dd, 1H); 77 (dt, 1H); 4.69 (d, 1H); 4.60 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.94 (m, 1H) 3.57 (m, 1H); 2.88 (s, 3H); 2.65 (m, 1H); 2.48 (s, 3H); 1.83 (m, 1H); 1.62 (M, 2H); 1.22 (m, 1H).
MS (ES / +): m / z = 493 [MH] ^<+> , 475 [M-OH] ^<+> .

Intermediate 11b (Diastereomer B)
NMR (d ₆ -DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.21 (dd, 1H); 6.88 (dd, 1H); 77 (dt, 1H); 4.78 (d, 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.13 (dd, 1H); 3.58 (m, 1H) 3.37 (m, 1H); 2.90 (s, 3H); 2.67 (m, 1H); 2.32 (s, 3H); 1.89 (m, 1H); 1.83 (M, 1H); 1.52 (dq, 1H); 1.29 (q, 1H).
MS (ES / +): m / z = 493 [MH] ^<+> , 475 [M-OH] ^<+> .

Intermediate 12
(4-Fluoro-2-methyl-phenylimino) -acetic acid ethyl ester A solution of ethyl glyoxalate (50% solution in toluene-40.8 mL) in toluene (180 mL) was placed in a flask equipped with a Dean-Stark apparatus in nitrogen. The mixture was heated to reflux for 1.5 hours under an atmosphere. A solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was then added slowly. The mixture was heated to reflux for 3 hours and then concentrated under vacuum. The residue was purified by flash chromatography (toluene / CH / AcOEt 4: 4: 2) to give the title compound (13.06 g) as a yellow oil.
t. l. c. : Toluene / CH / AcOEt 4: 4: 2, Rf = 0.67.
NMR (CDCl ₃ ): δ (ppm) 7.8 (s, 1H); 6.95 (d, 1H); 6.85 (d, 2H); 4.4 (q, 2H); 2.35 ( s, 3H); 3.3 (t, 3H).
MS (ES / +): m / z = 210 [M + H] ^< +>.

Intermediate 13
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-1,2,3,4-tetrahydro-pyridine-2-carboxylic acid ethyl ester Boron trifluoride ether (1.22 mL) To a solution of intermediate 12 (2 g) in anhydrous DCM (20 mL) cooled to 78 ° C. was added under a nitrogen atmosphere. After stirring at −78 ° C. for 15 minutes, 1-methoxy-3-trimethylsiloxy-1,3-butadiene (2.67 mL) was added dropwise over 45 minutes. The resulting solution was stirred at −78 ° C. for 2 hours and TFA (0.74 mL) was added. The mixture was stirred at 0 ° C. for 15 min, then saturated sodium bicarbonate solution was added and the mixture was extracted with AcOEt (3 × 50 mL). The combined organic extracts were dried and concentrated in vacuo to a residue that was purified by flash chromatography (CH / AcOEt 8: 3 to 7: 3) to give the title compound (1.5 g ) Was obtained as a pale yellow solid.
t. l. c. : CH / AcOEt 6: 4, Rf = 0.2.
NMR (CDCl ₃ ): δ (ppm) 7.4 (dd, 1H); 7.1 (d, 1H); 7.0-6.8 (m, 2H); 5.15 (d, 1H); 4.4 (m, 1H); 4.1 (m, 2H); 3.1-2.85 (m, 2H); 2.4 (s, 3H); 1.15 (t, 3H).

Intermediate 14
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid ethyl ester L-selectride (1M solution in dry THF, 3.96 mL) was previously cooled to -78 ° C. To a solution of intermediate 13 (1 g) in dry THF (30 mL) was added dropwise over 1 hour under a nitrogen atmosphere. After 1 hour, saturated sodium bicarbonate solution (20 mL) was added dropwise and the solution was extracted with AcOEt (3 × 50 mL). The combined organic extracts were dried and concentrated in vacuo to a residue that was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound (810 mg) as a white solid. .
t. l. c. : CH / AcOEt 6: 4, Rf = 0.6.
NMR (CDCl ₃ ): δ (ppm) 7.4 (dd, 1H); 7.1 (dd, 1H); 6.9 (dd, 1H); 6.8 (dt, 1H); 4.2 ( q, 2H); 4.15 (m, 1H); 3.6 (m, 1H); 3.2 (m, 1H); 2.8-2.7 (dd, 2H); 2.6 (m , 2H); 2.4 (s, 3H); 1.2 (t, 3H).

Intermediate 15
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid Lithium hydroxide monohydrate (241 mg) was added Intermediate 14 (300 mg) in MeOH (15 mL) and water (3 mL ) And the resulting solution was stirred at 80 ° C. for 1 hour. The solution was cooled to room temperature and extracted with Et20. The aqueous layer was acidified with acetic acid until pH 6 and extracted with AcOEt (3 × 15 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (230 mg) as a yellow solid that was used in the next step without further purification.
MS (ES / +): m / z = 252 [M + H] ^< +>.

Intermediate 16
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide DIPEA (0.47 mL) and O- (benzotriazole-1- Yl) -N, N, N′N′-tetramethyluronium tetrafluoroborate (385.3 mg) was added to a solution of intermediate 16 (230 mg) in anhydrous DMF (20 mL) under a nitrogen atmosphere. After stirring for 15 minutes, (3,5-dichlorobenzyl) -methylamine hydrochloride (225 mg) was added and the mixture was stirred at room temperature for 4 hours. The solution was diluted with water (30 mL) and extracted with AcOEt (3 × 60 mL). The combined organic extracts were washed with cold water (50 mL) and brine (3 × 80 mL) and then concentrated under vacuum. The residue was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (176 mg) as a pale yellow solid.
t. l. c. : CH / AcOEt 3: 7, Rf = 0.52.
NMR (d ₆ -DMSO): δ (ppm) 7.5-7.45 (2t, 1H); 7.14-6.88 (2d, 2H); 7.05 (dd, 1H); 6.92 (Dd, 1H); 6.82 (dt, 1H); 4.66-4.51 (2m, 1H); 4.59 (d, 1H); 4.15-4.1 (d + m, 1H); 3.83-3.57 (2m, 1H); 3.05 (m, 1H); 2.73 (m, 1H); 2.51 (m, 1H); 2.4-2.25 (m, 2H); 2.66-2.37 (2s, 3H); 2.37-2.24 (2s, 3H).
MS (ES / +): m / z = 423 [M + H] ^< +>.

Intermediate 17
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (17a -Diastereomers 1)
And 1- (4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide ( 17b-diastereomers 2)

DIPEA (0.531 mL) and O- (benzotriazol-1-yl) -N, N, N′N′-tetramethyluronium tetrafluoroborate (423 mg) were added to intermediate 15 (298 mg) under a nitrogen atmosphere. To the solution in anhydrous DMF (15 mL) was added and the resulting solution was stirred at room temperature for 15 minutes.
At the same time, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine maleate (500 mg) was treated with saturated sodium bicarbonate solution (10 mL) and AcOEt (2 × 30 mL). The organic layer was dried and concentrated in vacuo to give [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine (303 mg). This intermediate was added to the above solution and the mixture was stirred at 23 ° C. for 36 hours.
The solution was diluted with water (30 mL) and extracted with AcOEt (3 × 60 mL). The combined organic extracts were washed with cold water (2 × 50 mL) and brine (2 × 50 mL), dried and concentrated in vacuo. The residue is purified by flash chromatography (CH / AcOEt 1: 1):
1. Intermediate 17a yellow oil (56 mg);
2. A yellow oil (36 mg) of intermediate 17b was obtained.

Intermediate 17a
t. l. c. : CH / AcOEt 1: 1, Rf = 0.6.
NMR (d ₆ -DMSO): δ (ppm) 7.95 (s, 1H); 7.72 (s, 2H); 7.02 (m, 2H); 6.94 (m, 1H); 71 (q, 1H); 4.62 (m, 1H); 3.55 (m, 1H); 3.01 (m, 1H); 2.67 (m, 1H); 2.34-2.17 (M, 4H); 2.04 (s, 3H); 1.33 (d, 3H).

Intermediate 17b
t. l. c. : CH / AcOEt 1: 1, Rf = 0.4.
NMR (d ₆ -DMSO): δ (ppm) 8.02 (bs, 1H); 7.76 (bs, 2H); 6.95 (dd, 1H); 6.69 (dt, 1H); 46 (dt, 1H); 5.76 (q, 1H); 4.56 (m, 1H); 3.52 (m, 1H); 3.0 (m, 1H); 2.68 (m, 1H) 2.44 (m, 1H); 2.26 (m, 5H); 2.15 (s, 3H); 1.4 (d, 3H).

Intermediate 18
1- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide DIPEA (2.6 mL) and O- (benzo Triazol-1-yl) -N, N, N′N′-tetramethyluronium hexafluorophosphate (2.48 g) in a solution of intermediate 15 (1.259 g) in anhydrous DMF (25 mL) under nitrogen atmosphere. Added to. After stirring for 30 minutes, (3,5-bis-trifluoromethyl-benzyl) -methylamine hydrochloride (1.62 g) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with AcOEt (50 mL) and washed with saturated ammonium chloride solution (30 mL), saturated sodium bicarbonate solution (30 mL) and brine (3 × 50 mL). The organic extract was dried and concentrated under vacuum. The residue was purified by flash chromatography (CH / AcOEt 9: 1) to give the title compound (1.59 g) as a dark yellow oil.
t. l. c. : CH / AcOEt 1: 1, Rf = 0.25.
NMR (d ₆ -DMSO): δ (ppm) 8.03 (bs, 1H); 7.84 (bs, 2H); 7.03 (dd, 1H); 6.79 (dd, 1H); 64 (td, 1H); 4.80 (d, 1H); 4.67 (m, 1H); 4.29 (d, 1H); 3.55 (m, 1H); 3.04 (m, 1H) 2.74 (m, 1H); 2.5 (m, 1H); 2.4-2.2 (m, 2H); 2.40 (s, 3H); 2.38 (s, 3H) .
MS (ES / +): m / z = 491 [M + H] ^< +>.

Example 1
4- (R, S)-(2,2,2-trifluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- ( R)-(3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride Intermediate 4a (120 mg), 2,2,2-trifluoroethylamine (190 μL) in dry 1,2-dichloroethane ( The solution in 10 mL) was stirred at 23 ° C. for 1 hour under a nitrogen atmosphere and then sodium triacetoxyborohydride (75.7 mg) was added. The mixture was stirred at 23 ° C. for 18 hours, then a further 2,2,2-trifluoroethylamine (190 μL) and a few drops of acetic acid were added and the solution was stirred for a further 24 hours. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (CH / AcOEt 6: 4) to give 4- (2,2,2-trifluoroethyl) amino. -2- (R)-(4-Fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (27 mg: tlc: CH / AcOEt 1: 1, Rf = 0.77) was obtained as an enantiomeric mixture of C-2 and C-4 with an anti / syn ratio of 4: 6.
This material (25 mg) was dissolved in dry Et2O (5 mL) and treated with hydrochloric acid (1 M in Et2O: 1 mL). The resulting mixture was stirred at 23 ° C. for 30 minutes and then concentrated in vacuo to give the title compound as a whiteish solid (25 mg).

Melting point: 116-7 ° C
IR (Nujol): 1659 and 1651 (C = O) cm- ¹ .
NMR (d ₆ -DMSO): δ (ppm) 7.91 (s, 1H); 7.73 (s, 1H); 7.68 (s, 1H); 7.23 and 7.17 (2dd, 1H) 6.74-6.76 (m, 2H); 5.3 and 5.18 (2q, 1H); 4.9 and 4.18 (m and dd, 1H); 3.5-3.1 (M, 3H); 2.74 and 2.65 (2s, 3H); 2.35 and 2.28 (2s, 3H); 2.1-1.5 (m, 4H); 1.5 and 1 .46 (2d, 3H).
MS (ES / +): m / z = 588 [MH-HCl] ^<+> .

Example 2
4- (R)-(2,2-dimethyl-propylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-( 3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (2a)
4- (S)-(2,2-dimethyl-propylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R)-( 3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (2b)
A solution of intermediate 4a (120 mg), 2,2-dimethyl-propylamine (20.9 mg) and sodium triacetoxyborohydride (78.2 mg) in dry 1,2-dichloroethane (5 mL) was added under a nitrogen atmosphere. The mixture was stirred at 23 ° C. for 2 hours. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 85:15), and three fractions:
1. Diastereomer 1 (65.4 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.41),
2.2 mixture of two diastereomers (15.0 mg),
3. Diastereomer 2 (22.0 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.39) was obtained.

Example 2a
A solution of diastereomer 1 (64.0 mg) in Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O, 1 mL). The resulting solution was stirred at 23 ° C. for 30 minutes and then concentrated in vacuo to give the title compound as a white solid (67.4 mg).
IR (Nujol): 3376 (NH ₂ ⁺ ), 1627 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.16, 8.10 (2bm, 2H); 7.9 (s, 1H); 7.78 (s, 2H); 7.39 (dd, 1H) 7.00 (dd, 1H); 6.93 (dt, 1H); 5.24 (t, 1H); 5.09 (q, 1H); 3.54 (m, 2H); 3.05 (T, 1H); 2.81 (m, 2H); 2.60 (s, 3H); 2.31 (m, 1H); 2.20 (s, 3H); 2.13 (m, 2H) 1.57 (d, 3H); 1.62 (m, 1H); 0.98 (s, 9H).
MS (ES / +): m / z = 576 [MH-HCl] ^<+> .

Example 2b
A solution of diastereomer 2 (21.0 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O, 1 mL). The resulting mixture was stirred at room temperature for 15 minutes, then filtered and further treated with dry Et2O to give the title compound as a whitish solid (11 mg).
NMR (d ₆ -DMSO): δ (ppm) 7.9 (bs, 3H); 7.67 (bs, 1H); 7.16 (m, 1H); 6.96 (m, 1H); 95 (m, 1H); 5.29 (m, 1H); 4.20 (m, 1H); 3.5-2.7 (m, 5H); 2.62 (s, 3H); 2.35 (S, 3H); 2.7-2.0 (m, 4H); 1.45 (d, 3H); 0.95 (s, 9H).
MS (ES / +): m / z = 576 [MH-HCl] ^<+> .

Example 3
4- (R) -Ethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride (3a)
And 4- (S) -ethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoro Methyl-phenyl) -ethyl] -methylamide hydrochloride (3b)
A suspension of intermediate 4a (100 mg), ethylamine hydrochloride (326 mg), TEA (613 μL) and sodium triacetoxyborohydride (63 mg) in dry 1,2-dichloroethane (2.5 mL) under a nitrogen atmosphere. The mixture was stirred at 23 ° C. for 6 hours. The solution was diluted with DCM (10 ml) and washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 9: 1) and two fractions:
1. Diastereomer 1 (50 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.2)
2. Diastereomer 2 (10 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.13) was obtained.

Example 3a
A solution of diastereomer 1 (50 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 2 mL) and the resulting solution was stirred at 23 ° C. for 30 min and then concentrated in vacuo. The residue was triturated with Et2O to give the title compound as a white solid (24 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.56 (bs, 2H); 7.9 (s, 1H); 7.75 (s, 2H); 7.32 (dd, 1H); 98 (dd, 1H); 6.90 (m, 1H); 5.12 (q, 1H); 5.04 (t, 1H); 3.6-3.4 (m, 2H); 3.13 (T, 1H); 2.97 (m, 2H); 2.61 (s, 3H); 2.25 (s, 3H); 2.10 (m, 2H); 1.98 (m, 1H) 1.65 (m, 1H); 1.55 (d, 3H); 1.19 (t, 3H).
MS (ES / +): m / z = 534 [MH-HCl] ^<+> .

Example 3b
A solution of diastereomer 2 (10 mg) in dry Et 2 O (2 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.5 mL). The resulting mixture was stirred at 23 ° C. for 30 minutes and then concentrated under vacuum. The residue was triturated with Et2O to give the title compound as a white solid (7 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.60 (bs, 2H); 7.9 (s, 1H); 7.67 (s, 2H); 7.15 (dd, 1H); 94 (dd, 1H); 6.83 (dt, 1H); 5.29 (q, 1H); 4.19 (dd, 1H); 3.43 (bd, 1H); 3.30 (m, 1H) 2.97 (bm, 2H); 2.80 (t, 1H); 2.74 (s, 3H); 2.35 (s, 3H); 2.11 (bd, 1H); 2.06 (Bd, 1H); 1.68 (m, 1H); 1.57 (m, 1H); 1.45 (d, 3H); 1.17 (t, 3H).
MS (ES / +): m / z = 534 [MH-HCl] ^<+> .

Example 4
4- (R) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride (4a)
And 4- (S) -dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoro Methyl-phenyl) -ethyl] -methylamide hydrochloride (4b)

A solution of intermediate 4a (93 mg), dimethylamine (2M in THF, 40 μL) and sodium triacetoxyborohydride (57 mg) in dry 1,2-dichloroethane (10 mL) was stirred at 23 ° C. for 6 hours under nitrogen atmosphere. . The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 95: 5 to 80:20) and purified into two fractions:
1. Diastereomer 1 (39 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.2),
2. Diastereomer 2 (26 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.15) was obtained.

Example 4a
A solution of diastereomer 1 (39 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 2 mL) and the resulting solution was stirred at 23 ° C. for 5 min. The solution was concentrated in vacuo to give a white solid that was triturated in Et 2 O (2 mL) and then filtered to give the title compound as a white solid (16 mg).
IR (Nujol): 3443 (NH ₂ ⁺ ), 1640 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.64 (bs, 1H); 7.9 (s, 1H); 7.76 (s, 2H); 7.35 (dd, 1H); 00 (dd, 1H); 6.92 (bt, 1H); 5.19 (bt, 1H); 5.07 (q, 1H); 3.58 (m, 1H); 3.17 (t, 1H) 2.77 (bs, 3H); 2.73 (bs, 3H); 2.55 (s, 3H); 2.21 (s + m, 3H + 1H); 2.07 (bm, 2H); 1.63 (Dq, 1H); 1.55 (d, 3H).
MS (ES / +): m / z = 534 [MH-HCl] ^<+> .

Example 4b
A solution of diastereomer 2 (26 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 2 mL) and the resulting solution was stirred at 23 ° C. for 5 min. The solution was concentrated in vacuo to give a white solid that was triturated with Et 2 O (2 mL) then filtered to give the title compound as a white solid (24 mg).
IR (Nujol): 3399 (NH ₂ ⁺ ), 1665 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.75 (bs, 1H); 7.9 (s, 1H); 7.67 (s, 2H); 7.22 (dd, 1H); 93 (dd, 1H); 6.81 (dt, 1H); 5.31 (q, 1H); 4.17 (dd, 1H); 3.44 (m, 2H); 2.76 (t, 1H) 2.73 (s, 3H); 2.72 (s, 3H + 3H); 2.35 (s, 3H); 2.08 (d, 1H); 2.01 (d, 1H); 1.85 (Dq, 1H); 1.64 (q, 1H); 1.46 (d, 3H).

Example 5
4- (R) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride (5a)
And 4- (S) -dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride Salt (5b)

A solution of intermediate 10 (1.0 g) and dimethylamine (2M in THF) (50 mL) in MeOH (40 mL) was stirred at 23 ° C. for 5 h, then sodium borohydride (85 mg) in dry MeOH (10 mL). The solution was added. The resulting mixture was stirred at 23 ° C. for 30 minutes, then 5% sodium bicarbonate solution (20 mL) was added. The mixture was concentrated under vacuum to eliminate the alcohol and then the aqueous phase was extracted with AcOEt (3 × 50 mL). The combined organic extracts are dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 7: 3) and contains three fractions:
1. Diastereomer 1 white solid (61 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.23)
2.2 Mixture of two diastereomers (190 mg)
3. A white solid of diastereomer 2 (436 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.2) was obtained.

Example 5a
A solution of diastereomer 1 (61 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O, 0.12 mL). The resulting mixture was stirred at 0 ° C. for 15 minutes and then filtered to give the title compound as a white solid (55 mg).
Melting point: 180-3 ° C.
NMR (d ₆ -DMSO): δ (ppm) 9.78 (bs, 1H); 7.97 (s, 1H); 7.79 (s, 2H); 7.35 (dd, 1H); 0 (dd, 1H); 6.92 (dt, 1H); 5.17 (bt, 1H); 4.56 (d, 1H); 4.41 (d, 1H); 3.56 (bm, 2H) ); 3.1 (t, 1H); 2.75 (m + s, 9H); 2.23 (s, 4H); 2.09 (bm, 2H); 1.66 (m, 1H).
MS (ES / +): m / z = 520 [M-Cl] ^<+> .

Example 5b
A solution of diastereomer 2 (436 mg) in dry Et 2 O (25 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.85 mL). The resulting mixture was stirred at 0 ° C. for 15 minutes and then filtered to give the title compound (380 mg) as a white solid.
Melting point: 147-150 ° C
IR (Nujol): 3406 (NH ₂ ⁺ ), 1656 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.87 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.27 (dd, 1H); 94 (dd, 1H); 6.82 (m, 1H); 4.63 (d, 1H); 4.37 (d, 1H); 4.2 (dd, 1H); 3.54 (m, 1H) 3.3 (m, 1H); 2.92 (s, 3H); 2.70 (m, 6H); 2.70 (m, 1H); 2.36 (s, 3H); 2.1 -2.00 (m, 2H); 1.85 (m, 1H); 1.6 (m, 1H).
MS (ES / +): m / z = 520 [M-Cl] ^<+> .
[[Alpha]] _D = -82.77 (1.07% in DMSO).

Example 6
4- (R)-(2-Fluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3.5 -Bis) -trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (6a)
And 4- (S)-(2-fluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3, 5-Bis) -trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (6b)
A suspension of Intermediate 4a (100 mg), 2-fluoroethylamine hydrochloride (98 mg), TEA (100 μL) and sodium triacetoxyborohydride (65 mg) in dry 1,2-dichloroethane (8 mL) under a nitrogen atmosphere 23 Stir for 2 hours at ° C. An additional amount of 2-fluoroethylamine hydrochloride (98 mg) and TEA (100 μL) were added and the mixture was stirred at 23 ° C. An additional amount of sodium triacetoxyborohydride (65.0 mg) was added and the mixture was stirred at 23 ° C. under a nitrogen atmosphere for 1.5 hours.
The solution was washed with saturated sodium bicarbonate solution (8 mL) and brine (8 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 95: 5) and two fractions:
1. Diastereomer 1 (26.0 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.44)
2. Diastereomer 2 (17.0 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.3) was obtained.

Example 6a
A solution of diastereomer 1 (26.0 mg) in dry Et 2 O (1 mL) was treated with hydrochloric acid (1M in Et 2 O, 20 μL) and the resulting solution was stirred at 0 ° C. for 15 min. The solution was concentrated in vacuo and the residue was triturated with n-pentane (1 mL) to give the title compound as a white solid (21 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.96 (bs, 2H); 7.9 (s, 1H); 7.75 (s, 2H); 7.34 (dd, 1H); 00 (dd, 1H); 6.91 (m, 1H); 5.16-5.06 (m, 2H); 4.84-4.6 (m, 2H); 3.64-3.10 ( m, 5H); 2.3-1.65 (m, 4H); 2.60 (s, 3H); 2.24 (s, 3H); 1.55 (d, 3H).
MS (ES / +): m / z = 552 [MH-HCl] ^<+> .

Example 6b
A solution of diastereomer 2 (17.0 mg) in dry Et 2 O (1 mL) was treated with hydrochloric acid (1M in Et 2 O, 20 μL) and the resulting solution was stirred at 0 ° C. for 15 min. The solution was concentrated in vacuo and the residue was triturated with n-pentane (1 mL) to give the title compound as a white solid (15 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.93 (s, 2H); 7.9 (s, 1H); 7.67 (s, 2H); 7.15 (dd, 1H); 94 (dd, 1H); 6.83 (m, 1H); 5.28 (q, 1H); 4.8-4.6 (m, 2H); 4.18 (dd, 1H); 3.4 (M, 3H); 2.8-2.7 (m, 2H); 2.2-2.0 (m, 2H); 1.8-1.5 (m, 2H); 2.73 (s , 3H); 2.34 (s, 3H); 1.45 (d, 3H).
MS (ES / +): m / z = 552 [MH-HCl] ^<+> .

Example 7
4- (R)-(2-Fluoro-ethylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl- Benzyl) -methylamide hydrochloride (7a)
And 4- (S)-(2-fluoro-ethylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl -Benzyl) -methylamide hydrochloride (7b)

A mixture of Intermediate 10 (65 mg), 2-fluoroethylamine hydrochloride (132 mg), TEA (184 μL) and sodium triacetoxyborohydride (42 mg) in dry acetonitrile (5 mL) was stirred at room temperature under a nitrogen atmosphere. After 6 hours, additional 2-fluoroethylamine hydrochloride (264 mg), TEA (368 μL) and sodium triacetoxyborohydride (15 mg) were added. After stirring at room temperature for 20 hours, the crude solution was quenched with 5% sodium bicarbonate solution (4 mL) and admixed with AcOEt (5 mL). The aqueous phase was extracted with AcOEt (3 × 5 mL) and the combined organic phases were washed with brine (5 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 95: 5) and two fractions:
1. Diastereomer 1 (35 mg, tlc: AcOEt / MeOH 9: 1, Rf = 0.4)
2. Diastereomer 2 (32 mg, tlc: AcOEt / MeOH 9: 1, Rf = 0.27)

Example 7a:
A solution of diastereomer 1 (30 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1 M in Et2O, 0.5 mL) at 0 ° C. and the resulting solution was stirred under a nitrogen atmosphere for 30 min. The solution was concentrated in vacuo and the residue was triturated with Et2O to give the title compound as a whitish solid (26 mg).
Melting point: 145-6 ° C
IR (Nujol): 3404 (NH ₂ ⁺ ), 1629 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.04 (bs, 2H); 7.9 (s, 1H); 7.77 (s, 2H); 7.35 (dd, 1H); 99 (dd, 1H); 6.91 (dt, 1H); 5.09 (bt, 1H); 4.75 (bd, 2H); 4.58 (d, 1H); 4.43 (d, 1H) 3.64 (bm, 1H); 3.45-3.3 (m, 3H); 3.11 (dd, 1H); 2.81 (s, 3H); 2.27 (s, 3H) 2.17 (bm, 1H); 2.1 (bm, 2H); 1.69 (m, 1H).
MS (ES / +): m / z = 538 [MH-HCl] ^<+> .

Example 7b
A solution of diastereomer 2 (32 mg) in dry Et 2 O (2 mL) was treated with hydrochloric acid (1M in Et 2 O, 70 μL) at 0 ° C. and the resulting solution was stirred for 15 minutes under a nitrogen atmosphere. The solution was concentrated in vacuo and the residue was triturated from Et 2 O / n-pentane to give the title compound as a white solid (27 mg).
IR (Nujol): 3410 (NH ⁺ ), 1660 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.0-8.8 (bm, 2H); 7.95 (bs, 1H); 7.59 (bs, 2H); 7.20 (dd, 1H) 6.94 (dd, 1H); 6.84 (m1H); 4.70 (bd, 2H); 4.63 (d, 1H); 4.33 (d, 1H); 4.20 (dd) , 1H); 3.51 (m, 1H); 3.37 (bm, 3H); 2.93 (s, 3H); 2.75 (m, 1H); 2.35 (s, 3H); 2 .16 (m, 1H); 2.11 (m, 1H); 1.73 (m, 1H); 1.54 (m, 1H).
MS (ES / +): m / z = 538 [MH-HCl] ^<+> .

Example 8
4- (S)-(N-2-fluoroethyl-N-methylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis -Trifluoromethyl-benzyl) -methylamide hydrochloride Formaldehyde (37% in water, 43 μL), 10% palladium on activated carbon (10 mg) and 1 drop of acetic acid into a solution of Example 7b (28 mg) in MeOH (1.5 mL). Added. The mixture was stirred at room temperature for 1 h under hydrogen atmosphere, then filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the desired 4- (S)-(N-2-fluoroethyl-N-methylamino) -2- (R)-(4 -Fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (13 mg) was obtained as a yellow gum. This material was dissolved in dry Et 2 O (2 mL) and treated with hydrochloric acid (1M in Et 2 O, 0.5 mL) and the resulting solution was stirred for 15 minutes under a nitrogen atmosphere. The solution was concentrated in vacuo and the residue was triturated from Et 2 O / n-pentane to give the title compound as a white solid (11.6 mg).
Melting point: 80-81 ° C. (decomposition).
t. l. c. : AcOEt / MeOH 8: 2, Rf = 0.37 (free base).
IR (Nujol): 3387 (NH ⁺ ), 1653 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 10.04 (bm, 1H); 7.96 (s, 1H); 7.6 (s, 2H); 7.28 (dd, 1H); 94 (dd, 1H); 6.83 (dt, 1H); 4.84 (bd, 2H); 4.64 (d, 1H); 4.37 (d, 1H); 4.22 (bdd, 1H) 3.6 (bm, 2H); 3.54 (bd, 1H); 3.43 (m, 1H); 2.93 (s, 3H); 2.78 (m, 4H); 2.37 (S, 3H); 2.15-2.0 (m, 2H); 1.94 (dt, 1H); 1.65 (dq, 1H).
MS (ES / +): m / z = 552 [MH-HCl] ^<+> .

Example 9
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R)-(2-methoxyethylamino) -piperidine-1-carboxylic acid [1- (R)-(3,5- Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (9a)
And 2- (R)-(4-fluoro-2-methyl-phenyl) -4- (S)-(2-methoxyethylamino) -piperidine-1-carboxylic acid [1- (R)-(3.5 -Bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (9b)

A solution of intermediate 4a (100 mg), 2-methoxyethylamine (17 μL) and sodium triacetoxyborohydride (65 mg) in dry 1,2-dichloroethane (5 mL) was stirred at 23 ° C. for 2 hours under a nitrogen atmosphere. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 8: 2) and two fractions:
1. Diastereomer 1 (C-2 and C-4 anti-configuration-40 mg)
2. Diastereomer 2 (C-2 and C-4 cis configuration-20 mg) was obtained.

Example 9a
A solution of diastereomer 1 (40 mg) in dry Et 2 O (3 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.5 mL) and the resulting solution was stirred at 0 ° C. for 5 min. The solution was concentrated in vacuo and the residue was triturated with n-pentane (2 mL) to give the title compound as a white solid (40 mg).
IR (Nujol): 3396 (NH ₂ ⁺ ), 1640 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.67-8.62 (bs, 2H); 7.99 (s, 1H); 7.76 (s, 2H); 7.34 (dd, 1H) ); 6.99 (dd, 1H); 6.91 (m, 1H); 5.12 (m, 1H); 5.09 (m, 1H); 3.6-3.4 (m, 4H) 3.16 (m, 3H); 2.25-1.60 (m, 4H); 3.3 (m, 3H); 2.59 (s, 3H); 2.23 (s, 3H); 1.55 (d, 3H);
MS (ES / +): m / z = 564 [M-Cl] ^<+> .

Example 9b
A solution of diastereomer 2 (20 mg) in dry Et2O (3 mL) was treated with hydrochloric acid (1M in Et2O, 0.5 mL). The resulting solution was stirred at 23 ° C. for 30 minutes and then concentrated under vacuum. The residue was triturated with n-pentane (2 mL) to give the title compound as a white solid (20 mg).
IR (Nujol): 3421 (NH ₂ ⁺ ), 1656-1650 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.64 (bs, 2H); 7.9 (s, 1H); 7.67 (s, 2H); 7.14 (dd, 1H); 94 (dd, 1H); 6.83 (m, 1H); 5.28 (q, 1H); 4.17 (dd, 1H); 3.55 (t, 2H); 3.42 (m, 1H) 3.13 (m, 2H); 2.8-2.7 (m, 2H); 2.2-1.5 (m, 4H); 3.3 (m, 3H); 2.73 ( s, 3H); 2.34 (s, 3H); 1.45 (d, 3H);
MS (ES / +): m / z = 564 [M-Cl] ^<+> .

Example 10
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -methylamino-piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride (10a)
And 2- (R)-(4-fluoro-2-methyl-phenyl) -4- (S) -methylamino-piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoro Methyl-phenyl) -ethyl] -methylamide hydrochloride (10b)

Intermediate 4a (120 mg), methylamine (1M solution in THF, 2.5 mL) and sodium triacetoxyborohydride (65 mg) in dry 1,2-dichloroethane (5 mL) were stirred at 23 ° C. for 2 hours under nitrogen atmosphere. did. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 75:25) and two fractions:
1. Diastereomer 1 (40 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.3)
2. Diastereomer 2 (20 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.21) was obtained.

Example 10a
A solution of diastereomer 1 (40 mg) in dry Et 2 O (3 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.5 mL) and the resulting solution was stirred at 0 ° C. for 5 min. The solution was concentrated in vacuo and the residue was triturated with n-pentane (2 mL) to give the title compound as a white solid (40 mg).
IR (Nujol): 3398 (NH ₂ ⁺ ), 1627 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.60 (bs, 2H); 7.9 (s, 1H); 7.75 (s, 2H); 7.32 (dd, 1H); 99 (dd, 1H); 6.90 (m, 1H); 5.13 (q, 1H); 5.016 (t, 1H); 3.42 (m, 2H); 3.14 (m, 1H) 2.61 (s, 3H); 2.57 (s, 3H); 2.24 (s, 3H); 2.12 (m, 2H); 1.95 (m, 1H); 1.62 (M, 1H); 1.54 (d, 3H).
MS (ES / +): m / z = 520 [MH-HCl].

Example 10b
A solution of diastereomer B (20 mg) in dry Et2O (3 mL) was treated with hydrochloric acid (1M in Et2O, 0.5 mL). The solution was concentrated in vacuo and the residue was triturated with n-pentane (2 mL) to give the title compound as a white solid (20 mg).
IR ^{_{(Nujol): 3398 (NH 2 +)}} , 1658-1650 (C = O) cm -1.
NMR (d ₆ -DMSO): δ (ppm) 8.60 (bs, 2H); 7.9 (s, 1H); 7.67 (s, 2H); 7.15 (dd, 1H); 94 (dd, 1H); 6.83 (m, 1H); 5.30 (q, 1H); 4.18 (dd, 1H); 3.42 (m, 1H); 3.26 (m, 1H) 2.76 (t, 1H); 2.73 (s, 3H); 2.55 (s, 3H); 2.35 (s, 3H); 2.10-2.00 (m, 1H) 1.68 (m, 1H); 1.53 (m, 1H); 1.45 (d, 3H);
MS (ES / +): m / z = 520 [MH-HCl] ^<+> .

Example 11
2- (4-Fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (11a; diastereomer A)
And 2- (4-fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (11b; diastereomer B)

A solution of Intermediate 3 (150 mg), methylamine (2M in THF, 300 μL) and sodium triacetoxyborohydride (100 mg) in dry THF (6 mL) was stirred at room temperature under a nitrogen atmosphere. After 5 hours, additional methylamine (2M in THF, 300 μL) and sodium triacetoxyborohydride (35 mg) were added. After 3 hours, the crude solution was quenched with 5% sodium bicarbonate solution (5 mL) and admixed with AcOEt (5 mL). The aqueous phase was extracted with AcOEt (3 × 15 mL) and the combined organic phases were washed with brine (5 mL). The organic layer was dried and concentrated to a residue under vacuum, which was purified by flash chromatography (AcOEt / MeOH 85:15) to give 2- (4-fluoro-2-methyl-phenyl)- 4-Methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide in two fractions:
1. Example 11a (100 mg);
2. Obtained in Example 11b (13 mg).

Example 11a:
NMR (d ₆ -DMSO): δ (ppm) 7.94 (bs, 1H); 7.65 (bs, 2H); 7.24 (dd, 1H); 6.89 (dd, 1H); 79 (dt, 1H); 4.64 (dd, 1H); 4.57 (d, 1H); 4.37 (d, 1H); 3.19 (m, 1H); 3.07 (m, 1H) 2.86 (s, 3H); 2.75 (m, 1H); 2.28 (s, 3H); 2.26 (s, 3H); 1.84 (m, 3H); 1.7 -1.5 (m, 1H).
MS (ES / +): m / z = 506 [MH] ^<+> .

Example 11b:
NMR (d ₆ -DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.19 (dd, 1H); 6.89 (dd, 1H); 77 (dt, 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.13 (dd, 1H); 3.42 (m, 1H); 2.9 (s, 3H) 2.69 (m, 1H); 2.55 (bm, 1H); 2.33 (s, 3H); 2.29 (s, 3H); 1.96 (m, 1H); 1.89 (M, 1H); 1.39 (m, 1H); 1.16 (m, 1H).
MS (ES / +): m / z = 506 [MH] ^<+> .

Example 12
2- (4-Fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride (Diastereomer A)
A solution of Example 11a (100 mg) in dry Et 2 O (3 mL) was treated with hydrochloric acid (1M in Et 2 O, 220 μL) at 0 ° C. The resulting solution was stirred for 15 minutes under a nitrogen atmosphere and then concentrated under vacuum. The residue was triturated with Et2O / n-pentane to give the title compound (81 mg) as a white solid.
NMR (d ₆ -DMSO): δ (ppm) 8.66 (bm, 2H); 7.94 (bs, 1H); 7.65 (bs, 2H); 7.24 (dd, 1H); 89 (dd, 1H); 6.79 (dt, 1H); 4.64 (dd, 1H); 4.57 (d, 1H); 4.37 (d, 1H); 3.19 (m, 1H) 3.07 (m, 1H); 2.86 (s, 3H); 2.75 (m, 1H); 2.28 (s, 3H); 2.26 (s, 3H); 1.84 (M, 3H); 1.7-1.5 (m, 1H).
MS (ES / +): m / z = 506 [MH] ^<+> , 370.

Example 13
2- (4-Fluoro-2-methyl-phenyl) -4-methylamino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride (Diastereomer B)
A solution of Example 11b (13 mg) in dry Et 2 O (2 mL) was treated with hydrochloric acid (1M in Et 2 O, 30 μL) at 0 ° C. and the resulting solution was stirred for 15 minutes under a nitrogen atmosphere. The solution was concentrated under vacuum and the residue was triturated with Et2O / n-pentane to give the title compound (10 mg) as a white solid.
NMR (d ₆ -DMSO): δ (ppm) 8.65 (bm, 2H); 7.94 (bs, 1H); 7.58 (bs, 2H); 7.19 (dd, 1H); 93 (dd, 1H); 6.82 (dt, 1H); 4.62 (d, 1H); 4.33 (d, 1H); 4.18 (dd, 1H); 3.49 (m, 1H) 3.25 (bm, 1H); 2.92 (s, 3H); 2.74 (m, 1H); 2.55 (s, 3H); 2.35 (s, 3H); 2.12 2.06 (m, 2H); 1.68 (m, 1H); 1.48 (q, 1H).
MS (ES / +): m / z = 506 [MH] ^<+> , 370.

Example 14
4-Amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride (14a; diastereomer A)
And 4-amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride (14b; diastereomer B)

Methanesulfonyl chloride (20 μL) was cooled in advance to 0 ° C., and 2- (4-fluoro-2-methyl-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl- Benzyl) -methylamide (Intermediates 11a and 11b, a mixture of syn and antidiastereomers, 85 mg) and a solution of TEA (50 μL) in dry THF (5 mL) was added under a nitrogen atmosphere. After 1.5 hours, the solution was quenched with brine (4 mL) and extracted with AcOEt (3 × 5 mL). The organic layer was dried and concentrated to a residue under vacuum, which was purified by flash chromatography (CH / AcOEt 7: 3) and methanesulfonic acid 1-[(3,5-bis-tri Fluoromethyl-benzyl) -methyl-carbamoyl] -2- (4-fluoro-2-methyl-phenyl) -piperidin-4-yl ester in two fractions:
1. Diastereomer 1 (11 mg);
2. Obtained in diastereomer 2 (76 mg).

Example 14a (Diastereomer A)
A solution of diastereomer 2 (11 mg) and sodium azide (2 mg) in dry DMF (2 mL) was stirred at 80 ° C. for 4 hours under nitrogen atmosphere. The crude solution was diluted with AcOEt (5 mL) and washed with cold brine (3 × 5 mL). The organic layer was dried and concentrated in vacuo to give crude 4-azido-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl). -Methylamide was obtained as a semi-solid white residue (20 mg) which was treated with triphenylphosphine (10 mg) in dry THF (3 mL) and stirred at room temperature for 48 hours under nitrogen atmosphere. Water (3 μL) was then added and the mixture was stirred for an additional 48 hours. The crude solution was mixed with AcOEt (5 mL) and washed with brine (5 mL). The organic layer was dried and concentrated in vacuo to give crude 4-amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl). -Methylamide was obtained. This residue was dissolved in dry Et 2 O (2 mL) and treated with hydrochloric acid (1M in Et 2 O, 100 μL) at 0 ° C. and the resulting solution was stirred for 15 minutes under a nitrogen atmosphere. The solution was concentrated under vacuum and the residue was triturated with Et2O / n-pentane to give the title compound (9 mg) as a pale yellow solid.
_{NMR (d 6 -DMSO): δ} (ppm) 9.92 (bs, 1H); 7.9-7.7 (b, 3H); 7.58 (s, 2H); 7.29 (m, 1H 6.94 (m, 1H); 6.82 (m, 1H); 4.39 (m, 1H); 4.34 (d, 1H); 4.16 (d, 1H); 3.50 (M, 1H); 3.31 (m, 1H); 2.93 (m, 1H); 2.92 (s, 3H); 2.33 (s, 3H); 2.05-1.65 ( m, 4H).
MS (ES / +): m / z = 492 [M-Cl] ^<+> .

Example 14b (Diastereomer B)
A solution of diastereomer 1 (75 mg) and sodium azide (13 mg) in dry DMF (5 mL) was stirred at 80 ° C. for 4 hours under nitrogen atmosphere. The solution was diluted with AcOEt (5 mL) and washed with cold brine (3 × 5 mL). The organic layer was dried and concentrated in vacuo to give crude 4-azido-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl). -Methylamide was obtained as a semi-solid white residue (80 mg). This residue (60 mg) was treated with triphenylphosphine (30 mg) in dry THF (6 mL) and stirred at room temperature for 48 hours under a nitrogen atmosphere. Water (3 μL) was then added and the mixture was stirred for an additional 48 hours. The crude solution was mixed with AcOEt (5 mL) and washed with brine (5 mL). The organic layer was dried and concentrated in vacuo to give crude 4-amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl). -Methylamide was obtained.
This residue was dissolved in dry Et 2 O (2 mL) and treated with hydrochloric acid (1M in Et 2 O, 300 μL) at 0 ° C. and the resulting solution was stirred for 15 minutes under a nitrogen atmosphere. The solution was concentrated under vacuum and the residue was triturated with Et2O / n-pentane to give the title compound (10 mg) as a white solid.
NMR (d ₆ -DMSO): δ (ppm) 7.98 (s, 1H); 7.9-7.7 (b, 3H); 7.74 (s, 2H); 7.31 (m, 1H) 6.98 (m, 1H); 6.90 (m, 1H); 4.93 (t, 1H); 4.57 (d, 1H); 4.42 (d, 1H); 3.56 (M, 1H); 3.30 (m, 1H); 3.13 (m, 1H); 2.83 (s, 3H); 2.26 (s, 3H); 2.02-1.62 ( m, 4H).
^{MS (ES / +): m} / z = 492 [M-Cl] +, 475 [M-HCl-NH 3] +.

Example 15
4- (R) -cyclobutylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis) -tri Fluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (15a)
And 4- (S) -cyclobutylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis)- Trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (15b)

A solution of intermediate 4a (120 mg), cyclobutylamine (20.4 μL) and sodium triacetoxyborohydride (75.5 mg) in dry 1,2-dichloroethane (10 mL) was stirred at 23 ° C. for 4 hours under nitrogen atmosphere. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried and concentrated under vacuum to a residue that was purified by flash chromatography (AcOEt / MeOH 9: 1),
1. Diastereomer 1 (55.9 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.44)
2.2 Mixture of two diastereomers (33.3 mg)
3. Diastereomer 2 (22.9 mg, tl.c.:AcOEt/MeOH 8: 2, Rf = 0.3) was obtained.

Example 15a
A solution of diastereomer 1 (53.5 mg) in dry Et 2 O (10 mL) was treated with hydrochloric acid (1M in Et 2 O, 2 mL) and the resulting solution was stirred at 23 ° C. for 30 min. The solution was concentrated in vacuo to give the title compound as a white solid (54 mg).
Melting point: 68-70 ° C. (decomposition).
IR (Nujol): 3400, 3000-2400 (NH ₂ ⁺ ), 1637 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.79 (bs, 2H); 7.9 (s, 1H); 7.74 (s, 2H); 7.28 (dd, 1H); 97 (dd, 1H); 6.89 (dd, 1H); 5.13 (q, 1H); 4.98 (bt, 1H); 3.83 (m, 1H); 3.45-3.35 (M, 2H); 3.11 (m, 1H); 2.62 (s, 3H); 2.25 (s, 3H); 2.18 (2m, 4H); 1.92-1.76 ( 2m, 2H); 1.61 (m, 2H); 1.53 (d, 3H); 1.24 (m, 1H); 0.84 (m, 1H).
MS (ES / +): m / z = 560 [MH-HCl] ^<+> .

Example 15b
A solution of diastereomer 2 (21.2 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 2 mL). The resulting mixture was stirred at 23 ° C. for 15 minutes and then filtered to give the title compound as a whitish solid (22 mg).
Melting point: 211-213 ° C. (decomposition).
IR (Nujol): 3400-2500 (NH ₂ ⁺ ), 1664 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.07 (bs, 2H); 7.98 (bs, 1H); 7.65 (bs, 2H); 7.13 (m, 1H); 93 (m, 1H); 6.81 (m, 1H); 5.27 (m, 1H); 4.17 (m, 1H); 3.80 (bm, 1H); 3.4-3.3 (M, 2H); 2.77 (m, 1H); 2.72 (m, 3H); 2.33 (s, 3H); 2.17 (m, 4H); 2.07-1.99 ( m, 2H); 1.8-1.4 (m, 2H); 1.44 (d, 3H); 1.24 (m, 1H); 0.84 (m, 1H).
MS (ES / +): m / z = 560.

Example 16
4- (R) -cyclopropylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoro Methyl-phenyl) -ethyl] -methylamide hydrochloride (16a)
And 4- (S) -cyclopropylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-tri Fluoromethyl-phenyl) -ethyl] -methylamide hydrochloride (16b)

A solution of intermediate 4a (120 mg), cyclopropylamine (16.6 μL) and sodium triacetoxyborohydride (78.2 mg) in dry 1,2-dichloroethane (5 mL) was stirred at 23 ° C. for 2 hours under nitrogen atmosphere. . The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 85:15), and three fractions:
1. Diastereomer 1 (59.5 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.40)
2.2 Mixture of two diastereomers (20.0 mg)
3. Diastereomer 2 (32.0 mg, tlc: AcOEt / MeOH 7: 3, Rf = 0.37) was obtained.

Example 16a
A solution of diastereomer 1 (59.5 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 1 mL) and the resulting solution was stirred at 23 ° C. for 30 min. The solution was concentrated in vacuo to give the title compound as a white solid (59.5 mg).
IR (Nujol): 3404, (NH ₂ ⁺ ), 1639 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.86 (bs, 2H); 8.77 (bs, 1H); 8.00 (s, 1H); 7.76 (s, 2H); 34 (dd, 1H); 6.99 (dd, 1H); 6.92 (dt, 1H); 5.15 (q, 1H); 5.04 (bt, 1H); 3.66 (bm, 1H) 3.42 (bm, 1H); 2.14 (dt, 1H); 2.74 (bm, 1H); 2.63 (s, 3H); 2.25 (s, 3H); 2.19 (Bm, 2H); 2.02 (bm, 1H); 1.68 (m, 1H); 1.55 (d, 3H); 0.84 (bm, 2H); 0.79 (bm, 2H) .
MS (ES / +): m / z = 546 [MH-HCl] ^<+> .

Example 16b
A solution of diastereomer 2 (32.0 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 1 mL). The resulting mixture was stirred at 23 ° C. for 15 minutes, then filtered and further treated with diethyl ether to give the title compound as an off-white solid (20 mg).
IR (Nujol): 3383 (NH ₂ ⁺ ), 1650 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 9.00 (s, 2H); 7.99 (s, 1H); 7.67 (s, 2H); 7.15 (dd, 1H); 94 (dd, 1H); 6.83 (m, 1H); 5.29 (q, 1H); 4.21 (dd, 1H); 2.73 (s, 3H); 2.45 (m, 2H) 2.35 (s, 3H); 2.9-2.2 (m, 2H); 1.8-0.7 (m, 8H); 1.45 (d, 3H).
MS (ES / +): m / z = 546 [MH-HCl] ^<+> .

Example 17
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R, S)-[methyl- (1-methyl-piperidin-4-yl) -amino] -piperidine-1-carboxylic acid [1- (R)-(3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide hydrochloride Intermediate 4a (120 mg), 1-methyl-4- (methylamino) -piperidine (34 .6 μL) and sodium triacetoxyborohydride (75.5 mg) in dry 1,2-dichloroethane (2.5 mL) was stirred overnight at 23 ° C. under a nitrogen atmosphere. The solution was washed with 5% sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried and concentrated under vacuum to a residue that was purified by flash chromatography (AcOEt / MeOH 10: 0 to 1: 1) and 2- (4-fluoro-2- Methyl-phenyl) -4- [methyl- (1-methyl-piperidin-4-yl) -amino] -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl-phenyl) ) -Ethyl] -methylamide (43 mg, as a mixture of diastereomers A and B) was dissolved in dry Et2O (5 mL) and treated with hydrochloric acid (1 M in Et2O, 1 mL). The resulting mixture was stirred at 23 ° C. for 30 minutes and then concentrated under vacuum. The residue was triturated with Et 2 O to give the title compound (25 mg) as a white solid anti / cin 60:40 mixture.
NMR (d ₆ -DMSO): δ (ppm) 10.40 and 9.50 (2bs, 2H); 7.90 (d, 1H); 7.73 and 7.67 (2s, 2H); 7.30 And 7.22 (2bt, 1H); 6.94-6.75 (2m, 2H); 5.31 and 5.11 (2q, 1H); 5.00 and 4.24 (2bd, 1H); 2 .36 and 2.27 (2s, 3H); 1.53 and 1.46 (2d, 3H); 2.74-2.61 (6s, 9H); 3.40-1.75 (14m, 16H) .
MS (ES / +): m / z = 617 [MH-HCl] ^<+> .

Example 18
4-Benzylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (18a, diastereomer A)
And 4-benzylamino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (18b, diastereomer B)

A solution of Intermediate 3 (30 mg), benzylamine (7.5 μL), acetic acid (6 μL) and sodium triacetoxyborohydride (22 mg) in dry 1,2-dichloroethane (2 mL) was stirred at room temperature under a nitrogen atmosphere. . After 0.5 hours, additional benzylamine (7.5 μL) and sodium triacetoxyborohydride (22 mg) were added. After 1.5 hours, the crude solution was quenched with 1N potassium hydroxide solution (2 mL) and admixed with AcOEt (5 mL). The aqueous phase was extracted with AcOEt (3 × 5 mL) and the combined organic phases were washed with brine (5 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 9: 1) and two fractions:
1. Diastereomer A (24 mg, tlc: AcOEt / MeOH 9: 1, Rf = 0.45)
2. Diastereomer B (10 mg, tlc: AcOEt / MeOH 9: 1, Rf = 0.3) was obtained.

Example 18a (Diastereomer A)
NMR (d ₆ -DMSO): δ (ppm) 7.95 (bs, 1H); 7.60 (bs, 2H); 7.20 (m, 6H); 6.90 (m, 1H); 79 (m, 1H); 4.64 (d, 1H); 4.30 (d, 1H); 4.10 (m, 1H); 3.65 (bs, 2H); 3.15 (m, 1H) 2.90 (s, 3H); 2.65 (m, 1H); 2.35 (m, 1H); 2.25 (s, 3H); 1.90 (m, 2H); 1.6 -1.5 (m, 2H).
MS (ES / +): m / z = 582 [MH] ^<+> , 446.

Example 18b (Diastereomer B)
NMR (d ₆ -DMSO): δ (ppm) 7.93 (bs, 1H); 7.58 (bs, 2H); 7.25 (m, 6H); 6.88 (dd, 1H); 77 (dt, 1H); 4.62 (d, 1H); 4.32 (d, 1H); 4.09 (dd, 1H); 3.71 (s, 2H); 3.40 (m, 1H) 2.90 (s, 3H); 2.65 (m, 1H); 2.59 (m, 1H); 2.31 (s, 3H); 1.95 (m, 2H); 1.43 (M, 1H); 1.20 (m, 1H).
MS (ES / +): m / z = 582 [MH] ^<+> , 446.

Example 19
4-[(1,3-Dioxolan-2-yl) -methyl] -amino-2- (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl -Benzyl) -methylamide Drying of intermediate 3 (10 mg), 2- (aminomethyl) -1,3-dioxolane (2.09 mg), sodium triacetoxyborohydride (6.45 mg) and acetic acid (1.7 μL) A solution in 1,2-dichloroethane (400 μL) was stirred at 23 ° C. for 18 hours. The solution was diluted with DCM (1 mL) and washed with a 0.5N solution of sodium hydroxide (1 mL). The two layers were separated using a polypropylene filter Whatman filter tube and the organic solution passed through an SCX cartridge (Varian, 100 mg). The cartridge was washed with MeOH (3 mL), then the product was released by adding a 0.25 M solution of ammonia in MeOH (1 mL) and washed with MeOH (1 mL). The solution was concentrated in vacuo to give the title compound (7 mg) as a mixture of diastereomers A and B (70:30 ratio).

Diastereomer A:
NMR (CDCl ₃ ): δ (ppm) 7.75 (bs, 1H); 7.53 (s, 2H); 7.25 (dd, 1H); 6.85-6.78 (m, 2H); 4.96 (dd, 1H); 4.57 (d, 1H); 4.43 (d, 1H); 5.01 (t, 1H); 3.99 (m, 2H); 3.90 (m , 2H); 2.88 (s, 3H); 2.34 (s, 3H); 2.84 (d, 2H); 3.48-3.38 and 3.18-3.08 and 2.14 -1.50 (m, 7H).
MS (ES / +): m / z = 577.
Diastereomer B:
NMR (CDCl ₃ ): δ (ppm) 7.75 (bs, 1H); 7.67 (bs, 1H); 7.42 (s, 2H); 7.17 (dd, 1H); 6.85- 6.78 (m, 2H); 4.28 (dd, 1H); 4.65 (d, 1H); 4.37 (d, 1H); 4.99 (t, 1H); 3.99 (m , 2H); 3.90 (m, 2H); 2.96 (s, 3H); 2.43 (s, 3H); 2.86 (d, 2H); 3.48-3.38 and 3. 18-3.08 and 2.14-1.50 (m, 7H).
MS (ES / +): m / z = 577.

Example 20
4- (R) -N-2-fluoroethyl-N-methylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis- Trifluoromethyl-benzyl) -methylamide hydrochloride Formaldehyde (37% in water, 208 μL), 10% palladium on activated carbon (34 mg) and 2 drops of acetic acid were added to a solution of Example 7a (98 mg) in MeOH (5 mL). The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere, then filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt / MeOH 9: 1) and 4- (R)-(N-2-fluoroethyl-N-methylamino) -2- (R)-(4-fluoro -2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (85 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0. 37) was obtained. This material was dissolved in dry Et2O (5 mL) and treated with hydrochloric acid (1M in Et2O, 0.5 mL) and the resulting solution was stirred under a nitrogen atmosphere for 15 min. The solution was concentrated in vacuo and the residue was triturated from Et 2 O / n-pentane to give the title compound as a white solid (85 mg).
IR (Nujol): 3348 (NH ⁺ ), 1628 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.9 (bs, 1H); 7.9 (s, 1H); 7.78 (s, 2H); 7.35 (dd, 1H); 0 (dd, 1H); 6.92 (dt, 1H); 5.08 (bt, 1H); 4.73 (d, 2H); 4.58 (d, 1H); 4.43 (d, 1H) 3.65 (bm, 1H); 3.42-3.3 (m, 3H); 3.11 (dt, 1H); 2.81 (s, 3H); 2.5 (m, 3H) 2.27 (s, 3H); 2.17 (m, 1H); 2.11 (m, 1H); 2.06 (m, 1H); 1.69 (m, 1H).
MS (ES / +): m / z = 552 [MH-HCl] ^<+> .

Example 21
4- (R)-(carbamoylmethyl-amino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -Methylamide hydrochloride (21a)
And 4- (S)-(carbamoylmethyl-amino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) ) -Methylamide hydrochloride (21b)

A solution of intermediate 10 (120 mg), glycinamide hydrochloride (81 mg) and TEA (102 μL) in dry 1,2-dichloroethane (2 mL) and acetonitrile (2 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then sodium triacetoxyborohydride (78 mg) was added and the mixture was stirred at 23 ° C. for 18 hours. The solution was washed with 5% sodium bicarbonate solution (10 mL) and extracted with DCM (2 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated to a residue under vacuum, which was purified by flash chromatography (AcOEt / MeOH 8: 2) and purified into two fractions. :
1. Diastereomer 1 (47 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.22);
2. Diastereomer 2 (35 mg, tlc: AcOEt / MeOH 8: 2, Rf = 0.13) was obtained.

Example 21a
A solution of diastereomer 1 (47 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O, 0.1 mL). The resulting mixture was stirred at 0 ° C. for 15 minutes and then filtered to give the title compound as a yellow solid (41.5 mg).
Melting point: 130-1 ° C.
IR (Nujol): 3325 (NH ₂ ⁺ ), 1697 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.97 (bs, 1H); 8.92 (bs, 1H); 7.98 (s, 1H); 7.85 (s, 1H); 78 (s, 2H); 7.62 (s, 1H); 7.34 (td, 1H); 7.0 (dd, 1H); 6.91 (td, 1H); 5.1 (t, 1H) 4.57 (d, 1H); 4.41 (d, 1H); 3.74 (bs, 2H); 3.59 (bs, 1H); 3.46 (bd, 1H); 3.09 (T, 1H); 2.78 (s, 3H); 2.26 (s, 3H); 2.19 (m, 1H); 2.03 (m, 2H); 1.66 (m, 1H) .
MS (ES / +): m / z = 549 [M + H] ^< +>.

Example 21b
A solution of diastereomer 2 (35 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.1 mL). The resulting mixture was stirred at 0 ° C. for 15 minutes and then filtered to give the title compound as a yellow solid (27 mg).
Melting point: 100-1 ° C.
IR (Nujol): 3300-3100 (NH ₂ ⁺ ), 1695 (C═O) cm ⁻¹ .
NMR (d ₆ -DMSO): δ (ppm) 8.97 (bd, 2H); 7.94 (s, 1H); 7.81 (s, 1H); 7.59 (s, 3H); 18 (t, 1H); 6.94 (d, 1H); 6.83 (t, 1H); 4.64 (d, 1H); 4.33 (d, 1H); 4.17 (dd, 1H) 3.71 (b, 2H); 3.51 (d, 1H); 3.41 (m, 1H); 2.92 (s, 3H); 2.72 (t, 1H); 2.34 (S, 3H); 2.11 (d, 1H); 2.05 (d, 1H); 1.77 (m, 1H); 1.59 (m, 1H).
MS (ES / +): m / z = 549 [M + H] ^< +>.

Example 22
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (22a)
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (22b)
A solution of Intermediate 10 (500 mg) and morpholine (230 μL) in dry acetonitrile (5 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then sodium triacetoxyborohydride (390 mg) was added and the mixture was stirred at 23 ° C. for 18 hours. The solution was washed with saturated sodium bicarbonate solution and extracted with AcOEt. The organic extract is washed with brine, dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 97: 3) and two fractions:
1. Example 22a (187 mg);
2. Example 22b (209 mg) was obtained.

Example 22a:
NMR (CDCl ₃ ): δ (ppm) 7.77 (bs, 1H); 7.55 (bs, 2H); 7.27 (m, 1H); 6.83 (m, 2H); 5.06 ( dd, 1H); 4.51 (m, 2H); 3.75 (m, 4H); 3.52 (m, 1H); 3.15 (m, 1H); 2.88 (s, 3H); 2.6 (m, 1H); 2.55 (m, 4H); 2.34 (s, 3H); 2.04-1.88 (2m, 4H).
Example 22b:
NMR (CDCl ₃ ): δ (ppm) 7.76 (bs, 1H); 7.44 (bs, 2H); 7.18 (dd, 1H); 6.83 (m, 2H); 4.67- 4.4 (2d, 2H); 4.3 (dd, 1H); 3.71 (m, 4H); 3.48 (m, 1H); 2.98 (s, 3H); 2.86 (m , 1H); 2.58 (m, 4H); 2.5 (m, 1H); 2.45 (s, 3H); 2.04-1.98 (2m, 4H); 1.67 (dq, 1H); 1.48 (q, 1H).

Example 23
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide beforehand 0 ° C. A solution of Example 22a (175 mg) in dry Et 2 O (3 mL), cooled to 0 ° C., was treated with hydrochloric acid (1M in Et 2 O, 343 μL). The resulting mixture was stirred at 0 ° C. for 30 minutes, then pentane (5 mL) was added and the solid was filtered to give the title compound as a white solid (102 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.31 (bd, 1H); 7.9 (s, 1H); 7.82 (s, 2H); 7.3 (dd, 1H); 02 (dd, 1H); 6.94 (dd, 1H); 5.25 (s, 1H); 4.59 (d, 1H); 4.42 (d, 1H); 3.99 (dd, 2H) ); 3.76 (m, 2H); 3.73 (d, 1H); 3.59 (dd, 1H); 3.53 (d, 1H); 3.44 (d, 1H); 3.08 (Dd, 3H); 2.75 (s, 3H); 2.24 (s, 3H); 2.17 (m, 3H); 1.68 (dd, 1H).

Example 24
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide beforehand 0 ° C. A solution of Example 22b (202 mg) in dry Et2O (7 mL) and THF (0.5 mL), cooled to 0 ° C., was treated with hydrochloric acid (1M in Et2O, 396 μL). The resulting mixture was stirred at 0 ° C. for 30 minutes and then concentrated in vacuo to give the title compound as a white solid (199 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.97 (bd, 1H); 7.95 (s, 1H); 7.6 (s, 2H); 7.25 (dd, 1H); 94 (dd, 1H); 6.93 (dd, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.19 (d, 1H); 3.94 (dd, 2H) ); 3.8 (m, 2H); 3.55 (d, 1H); 3.45 (dd, 1H); 3.42 (d, 2H); 3.07 (dd, 2H); 2.93 (S, 3H); 2.73 (dd, 1H); 2.37 (s, 3H); 2.21 (dd, 2H); 1.91 (dd, 1H); 1.7 (dd, 1H) .

Example 25
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid 1-[(R)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide (25a)
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid 1-[(R)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide (25b)
A solution of Intermediate 4a (238 mg) and morpholine (106 μL) in dry acetonitrile (5 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then sodium triacetoxyborohydride (179 mg) was added and the mixture was stirred at 23 ° C. for 18 hours. The solution was washed with saturated sodium bicarbonate solution and extracted with AcOEt. The organic extract was washed with brine, dried and concentrated to a residue under vacuum, which was HPLC (column chiral cell OD 25 cm x 20 mm, n-hexane / EtOH 97: 3, flow rate 7.5 mL / min, λ = 225 nm) and purified to 3 fractions:
1. Example 25b (119 mg);
2. Mixture of Examples 25a and 25b (30 mg);
3. Example 25a (76 mg) was obtained.

Example 25a:
NMR (d ₆ -DMSO): δ (ppm) 7.97 (s, 1H); 7.71 (s, 2H); 7.26 (dd, 1H); 6.91 (dd, 1H); 82 (m, 1H); 5.16 (q, 1H); 4.83 (m, 1H); 3.59 (m, 4H); 3.3 (m, 1H); 3.15 (m, 1H) 2.61 (s, 3H); 2.41 (m, 4H); 2.4 (m, 1H); 2.24 (s, 3H); 1.9-1.65 (m, 4H) 1.49 (d, 3H).
HPLC: column chiral cell OD 25 cm x 4.6 mm; mobile phase: n-hexane / EtOH 97: 3, flow rate: 1 mL / min, λ = 225 nm; retention time: 7.54 minutes.

Example 25b:
NMR (d ₆ -DMSO): δ (ppm) 7.98 (s, 1H); 7.67 (s, 2H); 7.16 (dd, 1H); 6.9 (dd, 1H); 74 (m, 1H); 5.32 (q, 1H); 4.12 (dd, 1H); 3.51 (m, 4H); 3.4 (m, 1H); 2.7 (m, 4H) 2.44 (m, 4H); 2.4 (m, 1H); 2.33 (s, 3H); 1.9 (m, 2H); 1.6 (m, 1H); 1.45 (D, 3H); 1.37 (m, 1H).
HPLC: column chiral cell OD 25 cm x 4.6 mm; mobile phase: n-hexane / EtOH 97: 3, flow rate: 1 mL / min, λ = 225 nm; retention time: 6.61 minutes.

Example 26
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid 1-[(R)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide hydrochloride A solution of Example 25a (62 mg) in dry Et 2 O (1.5 mL), previously cooled to 0 ° C., was treated with hydrochloric acid (1M in Et 2 O, 119 μL). The resulting mixture was stirred at 0 ° C. for 30 minutes, then pentane (4 mL) was added and the solid was filtered to give the title compound as a white solid (56 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.27 (bs, 1H); 8.0 (bs, 1H); 7.78 (bs, 2H); 7.38 (dd, 1H); 01 (dd, 1H); 6.93 (dt, 1H); 5.25 (t, 1H); 5.07 (q, 1H); 3.98-3.74 (2t, 4H); 3.63 3.5, 3.42 (3m, 4H); 3.13 (m, 3H); 2.56 (s, 3H); 2.34 (m, 1H); 2.22 (s, 3H); 2.15 (m, 1H); 1.68 (m, 1H); 1.57 (d, 3H).

Example 27
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid 1-[(R)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide hydrochloride A solution of Example 25b (101 mg) in dry Et 2 O (2 mL), previously cooled to 0 ° C., was treated with hydrochloric acid (1M in Et 2 O, 190 μL). The resulting mixture was stirred at 0 ° C. for 1 hour, then pentane (5 mL) was added and the solid was filtered to give the title compound as a white solid (93 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.62 (bs, 1H); 7.9 (bs, 1H); 7.68 (bs, 1H); 7.21 (dd, 1H); 95 (dd, 1H); 6.83 (dt, 1H); 5.31 (q, 1H); 4.18 (dd, 1H); 3.95 (t, 2H); 3.76 (t, 2H) 3.45 (m, 4H); 3.08 (m, 2H); 2.77 (t, 1H); 2.74 (s, 3H); 2.36 (s, 3H); 2.18 (M, 2H); 1.87 (m, 1H); 1.74 (q, 1H); 1.46 (d, 3H).

Example 28
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid 1-[(S)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide (28a)
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid 1-[(S)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide (28b)
A solution of intermediate 5b (290 mg) and morpholine (130 μL) in dry acetonitrile (5 mL) was stirred at room temperature for 1 hour under a nitrogen atmosphere. Then sodium triacetoxyborohydride (217 mg) was added and the mixture was stirred at 23 ° C. for 18 hours. The solution was washed with saturated sodium bicarbonate solution and extracted with AcOEt. The organic extract is washed with brine, dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 97: 3):
1. Example 28a (87 mg);
2. Example 28b (100 mg) was obtained.

Example 28a:
NMR (CDCl ₃ ): δ (ppm) 7.75 (bs, 1H); 7.6 (bs, 2H); 7.24 (dd, 1H); 6.83 (m, 2H); 5.54 ( q, 1H); 5.03 (dd, 1H); 3.76 (m, 4H); 3.44 (m, 1H); 3.09 (m, 1H); 2.72 (s, 3H); 2.59 (m, 1H); 2.56 (m, 4H); 2.35 (s, 3H); 2.05 (m, 2H); 1.85 (m, 2H); 1.54 (d , 3H).
Example 28b:
NMR (CDCl ₃ ): δ (ppm) 7.73 (bs, 1H); 7.44 (bs, 2H); 7.14 (dd, 1H); 6.84 (dd, 1H); 6.79 ( dt, 1H); 5.62 (q, 1H); 4.3 (dd, 1H); 3.71 (m, 4H); 3.44 (m, 1H); 2.83 (m, 1H); 2.82 (s, 3H); 2.57 (m, 4H); 2.45 (m + s, 4H); 2.01 (m, 2H); 1.64 (m, 1H); 1.52 (d , 3H); 1.45 (q, 1H).

Example 29
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (R) -morpholino-piperidine-1-carboxylic acid 1-[(S)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide hydrochloride A solution of Example 28a (80 mg) in dry Et 2 O (1.5 mL), previously cooled to 0 ° C., was treated with hydrochloric acid (1M in Et 2 O, 150 μL). The resulting mixture was stirred at 0 ° C. for 1 hour and then filtered to give the title compound as a pale yellow solid (71 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.17 (bs, 1H); 7.9 (s, 1H); 7.84 (s, 2H); 7.41 (dd, 1H); 04 (dd, 1H); 6.94 (dt, 1H); 5.29 (q, 1H); 5.25 (m, 1H); 4.01 (m, 2H); 3.76 (m, 2H) 3.73 (m, 1H); 3.5 (m, 2H); 3.48 (m, 1H); 3.13 (m, 2H); 2.97 (t, 3H); 2.63 (S, 1H); 2.34 (m, 2H); 2.23 (s, 3H); 2.16 (m, 1H); 1.66 (m, 1H); 1.54 (d, 3H) .

Example 30
2- (R)-(4-Fluoro-2-methyl-phenyl) -4- (S) -morpholino-piperidine-1-carboxylic acid 1-[(S)-(3,5-bis-trifluoromethyl- Phenyl) -ethyl] -methylamide hydrochloride A solution of Example 28b (90 mg) in dry Et2O (1.5 mL), previously cooled to 0 ° C., was treated with hydrochloric acid (1M in Et2O, 172 μL). The resulting mixture was stirred at 0 ° C. for 1 hour, then pentane (5 mL) was added and the mixture was filtered to give the title compound as a white solid (89 mg).
NMR (d ₆ -DMSO): δ (ppm) 10.55 (bs, 1H); 7.94 (s, 1H); 7.54 (s, 2H); 7.21 (dd, 1H); 6. 93 (dd, 1H); 6.8 (dt, 1H); 5.33 (q, 1H); 4.18 (dd, 1H); 3.95-3.75 (2m, 4H); 3.54 (M, 1H); 3.47 (m, 1H); 3.43-3.07 (2m, 4H); 2.84 (s, 3H); 2.68 (t, 1H); 2.36 ( s, 3H); 2.2 (m, 2H); 1.88 (dq, 1H); 1.64 (q, 1H); 1.5 (d, 3H).

Example 31
4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide (31a; diastereomer A)
And 4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide (31b; diastereomer B)
Cyclopropylamine (0.012 mL) and sodium triacetoxyborohydride (38.1 mg) were added to a solution of intermediate 5 (50 mg) in anhydrous acetonitrile (3 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 hours, then additional cyclopropylamine (0.006 mL) and sodium triacetoxyborohydride (25.4 mg) were added. The mixture was stirred at 23 ° C. for 2 days. The solution was diluted with AcOEt (15 mL) and washed with 5% sodium bicarbonate solution (15 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 85:15) and two fractions:
1. Colorless oil of Example 31a (8.5 mg);
2. A colorless oil of Example 31b (10.1 mg) was obtained.

Example 31a
t. l. c. : AcOEt / MeOH 85:15, Rf = 0.23.
NMR (d ₆ -DMSO): δ (ppm) 7.36 (bs, 1H); 7.12 (dd, 1H); 6.95 (bs, 2H); 6.89 (bd, 1H); 82 (bt, 1H); 4.48 (d, 1H); 4.32 (bm, 1H); 4.31 (bm, 1H); 3.48 (bm, 1H); 3.1 (bm, 1H) 2.83 (m, 3H); 2.78 (bm, 1H); 2.24 (s, 3H); 2.12 (m, 1H); 1.94 (m, 2H); 1.77 (M, 1H); 1.53 (m, 1H); 0.4 (m, 2H); 0.26 (m, 2H).
MS (ES / +) m / z = 464 [M + H] ^< +>.

Example 31b:
t. l. c. : AcOEt / MeOH 85:15, Rf = 0.18.
NMR (d ₆ -DMSO): δ (ppm) 7.33 (bs, 1H); 7.11 (bm, 1H); 6.91 (bd, 2H); 6.85 (bs, 1H); 82 (bm, 1H); 4.4 (bm, 1H); 4.2 (bm, 1H); 4.15 (bd, 1H); 3.03 (bm, 1H); 2.96 (bs, 3H) 2.75 (bt, 1H); 2.5 (bm, 1H); 2.28 (bs, 3H); 2.11 (bm, 2H); 1.91 (bm, 1H); 1.53 (Bq, 1H); 1.47 (bq, 1H); 0.39 (m, 2H); 0.23 (m, 2H).
MS (ES / +) m / z = 464 [M + H] ^< +>.

Example 32
4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide hydrochloride (diastereomer A)
A solution of Example 31a (8 mg) in dry Et 2 O (1 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.019 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes then concentrated in vacuo and the residue was triturated with pentane (2 × 3 mL) to give the title compound as a white solid (6.6 mg).
NMR (d ₆ -DMSO-70 ° C.): δ (ppm) 8.93 (bs, 2H); 7.42 (s, 1H); 7.2-6.8 (bm, 5H); 4.7- 3.4 (m, 5H); 3.0-2.6 (m, 5H); 2.3-2.0 (m, 6H); 1.76 (m, 1H); 1.0-0. 8 (m, 4H).
MS (ES / +) m / z = 464 [M + H-HCl] ^<+> .

Example 33
4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide hydrochloride (diastereomer B)
A solution of Example 31b (9 mg) in dry Et 2 O (1 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.021 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes, concentrated in vacuo, and the residue was triturated with pentane (2 × 3 mL) to give the title compound as a white solid (9.3 mg).
NMR (d ₆ -DMSO-70 ° C.): δ (ppm) 9.0 (bs, 2H); 7.36 (s, 1H); 7.15 (bt, 1H); 6.95 (dd, 1H) 6.85 (m, 1H); 6.83 (s, 2H); 4.3 (bd, 1H); 4.8-4.0 (bm, 2H); 3.45 (bm, 1H); 3.0 (m, 1H); 2.8-2.5 (m, 2H); 3.04 (s, 3H); 2.31 (s, 3H); 2.3 (bm, 1H); 2 .13 (bd, 1H); 1.92 (q, 1H); 1.82 (dq, 1H); 0.92-0.8 (m, 4H).
MS (ES / +) m / z = 464 [M + H-HCl] ^<+> .

Example 34
4- (4-acetyl-piperazin-1-yl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide (34a; diastereo Mer A)
And 4- (4-acetyl-piperazin-1-yl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide (34b; Stereomer B)

N-acetyl-piperazine (35.8 mg) and sodium triacetoxyborohydride (58.1 mg) were added to a solution of intermediate 16 (58 mg) in anhydrous acetonitrile (3 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 24 hours, then diluted with AcOEt (15 mL) and washed with 5% sodium bicarbonate solution (15 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is subjected to flash chromatography (AcOEt / MeOH 85:15) to give two fractions:
1. Colorless oil of Example 34a (2 mg);
2. A colorless oil of Example 34b (9 mg) was obtained.

Example 34a
t. l. c. : AcOEt / MeOH 8: 2, Rf = 0.33.
Example 34b:
t. l. c. : AcOEt / MeOH 8: 2, Rf = 0.23.
NMR (d ₆ -DMSO): δ (ppm) 7.33 (s, 1H); 7.09 (m, 1H); 6.92-6.79 (m, 4H); 4.5-4.2 (Bm, 2H); 4.16 (d, 1H); 3.43 (m, 4H); 3.04 (m, 2H); 2.9 (bs, 3H); 2.5 (m, 5H) 2.29 (bs, 3H); 2.11-1. 6 (m, 4H); 1.26 (s, 3H).
MS (ES / +) m / z = 535 [M + H] ^< +>.

Example 35
4- (4-Acetyl-piperazin-1-yl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-dichloro-benzyl) -methylamide hydrochloride (diastereo Mar B)
A solution of Example 34b (5.3 mg) in dry Et 2 O (1 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.011 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes then concentrated in vacuo and the residue was triturated with pentane (2 × 3 mL) to give the title compound as a white solid (4.5 mg).
MS (ES / +) m / z = 535 [M + H-HCl] ^<+> .

Example 36
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (36a; diastereomer A)
And 4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl]- Methylamide (36b; diastereomer B)

Cyclopropylamine (0.015 mL) was added to a solution of intermediate 17a (56 mg) in anhydrous acetonitrile (1 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (34 mg) was added. The mixture was stirred at 23 ° C. for 18 hours, then diluted with DCM (15 mL) and washed with 5% sodium bicarbonate solution (15 mL) and brine (10 mL). The organic layer is dried and concentrated to a residue under vacuum, which is purified by flash chromatography (AcOEt / MeOH 9: 1) and two fractions:
1. The yellow oil of Example 36a (12 mg);
2. A yellow oil of Example 36b (23 mg) was obtained.

Example 36a:
t. l. c. : AcOEt / MeOH 9: 1, Rf = 0.32.
HPLC: column: spercodyl ABZ plus 15 cm x 46 mm x 5μ; mobile phase: acetonitrile / 10 mM ammonium acetate solution, 40:60 to 90:10 in 5 minutes, then 10 minutes, 90:10; flow rate = 0.8 mL / Min; λ = 360 nm; retention time: 10.2 min.

Example 36b:
t. l. c. : AcOEt / MeOH 9: 1, Rf = 0.22.
HPLC: column: spercodyl ABZ plus 15 cm x 46 mm x 5μ; mobile phase: acetonitrile / 10 mM ammonium acetate solution, 40:60 to 90:10 in 5 minutes, then 10 minutes, 90:10; flow rate = 0.8 mL / Min; λ = 360 nm; retention time: 9.4 min.

Example 37
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide Hydrochloride (Diastereomer A)
A solution of Example 36a (12 mg) in dry Et 2 O (0.5 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.024 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes then concentrated in vacuo and the residue was triturated with pentane (2 × 1 mL) to give the title compound as a yellow solid (7.7 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.9 (bm, 1H); 8.0-7.96 (2s, 1H); 7.78-7.41 (2s, 2H); 7.4 -6.65 (m, 3H); 5.73-5.32 (2q, 1H); 4.5-4.46 (2m, 1H); 4.2-4.16 (2bm, 1H); 3 2.5-2.4 (bm + m, 3H); 2.53-2.29 (2s, 3H); 2.29-2.03 (2s, 3H); 2.17 (m, 2H); 2.0 (M, 1H); 1.7 (m, 1H); 1.57-1.33 (2d, 3H); 0.87 (m, 2H); 0.78 (m, 2H).
MS (ES / +) m / z = 547 [M + H-HCl] ^<+> .

Example 38
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide Hydrochloride (Diastereomer B)
A solution of Example 36b (22 mg) in dry Et 2 O (0.5 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.044 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes then concentrated in vacuo and the residue was triturated with pentane (2 × 1 mL) to give the title compound as a yellow solid (18 mg).
NMR (d ₆ -DMSO): δ (ppm) 9.0 (bm, 2H); 7.9 (bs, 1H); 7.63 (bs, 2H); 7.13 (m, 1H); 94 (m, 1H); 6.86 (bm, 1H); 5.56 (bq, 1H); 4.25 (bd, 1H); 3.7-2.4 (bm + bm + bm, 4H); 2.85 (Bs, 3H); 2.28 (bs, 3H); 2.27 (bm, 1H); 2.14 (bm, 1H); 1.96 (m, 1H); 1.84 (m, 1H) 1.28 (bd, 3H); 0.91 (m, 2H); 0.82 (m, 2H).
MS (ES / +) m / z = 547 [M + H-HCl] ^<+> .

Example 39
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (39a; diastereomer A)
And 4-cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl]- Methylamide (39b; diastereomer B)

Cyclopropylamine (0.010 mL) was added to a solution of intermediate 36b (36 mg) in anhydrous acetonitrile (1 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 10 minutes and then sodium triacetoxyborohydride (22 mg) was added. The mixture was stirred at 23 ° C. for 18 hours, then diluted with DCM (15 mL) and washed with 5% sodium bicarbonate solution (15 mL) and brine (10 mL). The organic layer was dried and concentrated under vacuum to a residue that was purified by flash chromatography (AcOEt / MeOH 9: 1),
1. Yellow oil of Example 39a (3.7 mg);
2. The yellow oil of Example 39b (2.7 mg) was obtained.

Example 39a:
t. l. c. : AcOEt / MeOH 9: 1, Rf = 0.43.
HPLC: column: spercodyl ABZ plus 15 cm x 46 mm x 5μ; mobile phase: acetonitrile / 10 mM ammonium acetate solution, 40:60 to 90:10 in 5 minutes, then 10 minutes, 90:10; flow rate = 0.8 mL / Min; λ = 360 nm; retention time: 10.2 min.
Example 39b:
t. l. c. : AcOEt / MeOH 9: 1, Rf = 0.31.
HPLC: column: spercodyl ABZ plus 15 cm x 46 mm x 5μ; mobile phase: acetonitrile / 10 mM ammonium acetate solution, 40:60 to 90:10 in 5 minutes, then 10 minutes, 90:10; flow rate = 0.8 mL / Min; λ = 360 nm; retention time: 8.9 min.

Example 40
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide Hydrochloride (Diastereomer A)
A solution of Example 39a (3.7 mg) in dry Et 2 O (0.5 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.0074 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 minutes, then concentrated in vacuo, and the residue was triturated with pentane (2 × 1 mL) to give the title compound as a yellow solid (2.1 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.8 (bm, 1H); 8.71 (bm, 1H); 8.04 (bs, 1H); 7.73 (bs, 2H); 95 (m, 2H); 6.65 (dt, 1H); 5.84 (q, 1H); 4.45 (m, 1H); 3.98 (bm, 1H); 3.59 (m, 1H) 2.91 (m, 1H); 2.78 (m, 1H); 2.39 (s, 3H); 2.18 (s, 3H); 2.2 (bm, 1H); 2.09 (M, 1H); 2.0 (m, 1H); 1.63 (m, 1H); 1.47 (d, 3H); 0.83 (m, 4H).
MS (ES / +) m / z = 547 [M + H-HCl] ^<+> .

Example 41
4-Cyclopropylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide Hydrochloride (Diastereomer B)
A solution of Example 39b (2.7 mg) in dry Et 2 O (0.5 mL) was treated with hydrochloric acid (1M in Et 2 O, 0.0054 mL) at 0 ° C. under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C. for 30 min, then concentrated in vacuo, and the residue was triturated with pentane (2 × 1 mL) to give the title compound as a yellow solid (2.0 mg).
NMR (d ₆ -DMSO): δ (ppm) 8.81 (bs, 2H); 7.89 (bs, 1H); 7.52 (bs, 2H); 7.09 (m, 1H); 89 (bd, 1H); 6.71 (bm, 1H); 5.62 (bq, 1H); 4.29 (bd, 1H); 3.45 (bm, 1H); 3.0 (bd, 1H) ); 2.9-2.4 (bm, 2H); 2.85 (s, 3H); 2.29 (s, 3H); 2.29 (bm, 1H); 2.13 (m, 1H) 1.88 (bq, 1H); 1.79 (m, 1H); 1.38 (bd, 3H); 0.85 (m, 4H).
MS (ES / +) m / z = 547 [M + H-HCl] ^<+> .

Example 42
4-Cyclopropylmethylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide (Diastereomer B)
Cyclopropylmethylamine (70 mg) and sodium cyanoborohydride polymer conjugate (175 mg) were added to a solution of intermediate 18 (120 mg) in DCM (1.35 mL) and glacial acetic acid (0.15 mL) and the resulting mixture was added. Shake for 16 hours at room temperature. The resin was then filtered and washed with DCM (1 mL). The filtrate was washed with a saturated sodium bicarbonate solution (1 mL) and then filtered through a Whatman filter tube. The organic layer was diluted with DCM (5 mL), aldehyde polymer conjugate (890 mg) was added and the suspension was shaken at room temperature for 10 hours. The resin was then filtered and washed with DCM (1 mL). The filtrate is concentrated under vacuum and the residue is HPLC (column: X-tellurra C-18 30 × 1.9 cm; mobile phase: 10 mM ammonium acetate solution / acetonitrile from 50:50 to 10:90 in 16 min; flow rate = 7 mL / min. ; Λ = 225 nm). There was thus obtained the title compound (44 mg).
NMR (d ₆ -DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt, 1H); 6.88 (bd, 1H); 71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H); 3.08 (s, 3H); 2.63 (bs, 2H) 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s, 3H); 2.06 (bs, 1H); 1.83 (d, 1H) 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m, 2H); 0.08 (m, 2H).
MS (ES / +) m / z = 478 [M + H] ^< +>.
HPLC: column: X-tellula C-18 25 x 0.46 cm; mobile phase: 10 mN ammonium acetate solution / acetonitrile from 50:50 to 10:90 in 12 minutes; flow rate = 0.8 mL / min; λ = 225 nm; retention time: 8.0 minutes.

Example 43
4-cyclopropylmethylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide (43a; diastereomer 1)
And 4-cyclopropylmethylamino-1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide (43b; diastereomer 2)
Example 42 (40 mg) was purified by HPLC (column: Chiralpak AD 25 × 2.0 cm; mobile phase: n-hexane / EtOH 85:15; flow rate = 7 mL / min; λ = 225 nm):
1. Example 43a (16 mg; retention time: 12.2 minutes)
2. Example 43b (16 mg; retention time: 15 minutes) was obtained.

Example 43a:
NMR (d ₆ -DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt, 1H); 6.88 (bd, 1H); 71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H); 3.08 (s, 3H); 2.63 (bs, 2H) 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s, 3H); 2.06 (bs, 1H); 1.83 (d, 1H) 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m, 2H); 0.08 (m, 2H).
MS (ES / +) m / z = 478 [M + H] ^< +>.
HPLC: column: Chiralpak AD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 90:10; flow rate = 1 mL / min; [lambda] = 225 nm; retention time: 5.4 minutes.

Example 43b:
NMR (d ₆ -DMSO): δ (ppm) 7.90 (s, 1H); 7.54 (bs, 2H); 7.05 (bt, 1H); 6.88 (bd, 1H); 71 (bt, 1H); 4.71 (bs, 1H); 4.21 (bs, 2H); 4.1 (bs, 1H); 3.08 (s, 3H); 2.63 (bs, 2H) 2.5-1.2 (m, 2H); 2.40 (m, 2H); 2.24 (s, 3H); 2.06 (bs, 1H); 1.83 (d, 1H) 1.39 (bd, 1H); 0.84 (m, 1H); 0.37 (m, 2H); 0.08 (m, 2H).
MS (ES / +) m / z = 478 [M + H] ^< +>.
HPLC: column: Chiralpak AD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 90:10; flow rate = 1 mL / min; λ = 225 nm; retention time: 7.0 minutes

Example 44
1- (4-Fluoro-2-methyl-phenyl) -4-morpholino-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (Diastereomer B)
Morpholine (85 mg) and sodium cyanoborohydride polymer conjugate (175 mg, 4.2 mmol / g) were added to a solution of intermediate 18 (120 mg) in DCM (1.35 mL) and glacial acetic acid (0.15 mL), The resulting mixture was shaken at room temperature for 16 hours. The resin was then filtered and washed with DCM (1 mL). The filtrate was washed with saturated sodium bicarbonate solution (1 mL) and filtered through Whatman filter tubes. The organic layer was diluted with DCM (8 mL), isocyanate polymer conjugate (1.22 mg, 2.0 mmol / g) was added and the suspension was shaken at room temperature for 10 hours. The resin was then filtered and washed with DCM (1 mL). The filtrate was concentrated in vacuo and the residue (85 mg) was HPLC (column: X-tellra C-18 30 × 1.9 cm; mobile phase: 10 mM ammonium acetate solution / acetonitrile from 50:50 to 10:90 in 14 minutes; flow rate = 7 mL / min; λ = 225 nm) to obtain the title compound (42 mg).

NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.3 (m, 2H) 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (M, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 494 [M + H] ^< +>.
HPLC: Column: X-Tellra C-18 25 x 0.46 cm; Mobile phase: 10 mM ammonium acetate solution / acetonitrile from 50:50 to 10:90 in 12 minutes; flow rate = 0.8 mL / min; λ = 225 nm; retention time : 11.9 minutes.

Example 45
1- (4-Fluoro-2-methyl-phenyl) -4-morpholino-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (45a; diastereomer 1)
And 1- (4-fluoro-2-methyl-phenyl) -4-morpholino-piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (45b; diastereomer 2)

Example 44 (38 mg) was purified by HPLC (column: Chiralpak AD 25 × 2.0 cm; mobile phase: n-hexane / EtOH 80:20; flow rate = 7 mL / min; λ = 225 nm):
1. Example 45a (13 mg, retention time: 13.5 minutes)
2. Example 45b (13 mg, retention time: 16.1 minutes) was obtained.

Example 45a
NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.3 (m, 2H) 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (M, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 494 [M + H] ^< +>.
HPLC: column: Chiralpak AD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 80/20; flow rate = 1 mL / min; [lambda] = 225 nm; retention time: 4.9 minutes.

Example 45b
NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.3 (m, 2H) 3.11 (s, 3H); 2.92 (bs, 1H); 2.5 (m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (M, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 494 [M + H] ^< +>.
HPLC: column: Chiralpak AD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 80/20; flow rate: 1 mL / min; [lambda] = 225 nm; retention time: 6.0 minutes.

Example 46
4- (4-acetylpiperazinyl) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide (diastereomer B)
N-acetylpiperazine (126 mg) and sodium cyanoborohydride polymer conjugate (175 mg) were added to a solution of intermediate 18 (120 mg) in DCM (1.35 mL) and glacial acetic acid (0.15 mL) and the resulting mixture was added. Shake for 16 hours at room temperature. The resin was then filtered and washed with DCM (1 mL). The filtrate was washed with a saturated sodium bicarbonate solution (1 mL) and then filtered through a Whatman filter tube. The organic layer was diluted with DCM (8 mL), isocyanate polymer conjugate (1.22 mg) was added and the suspension was shaken at room temperature for 10 hours. The resin was then filtered and washed with DCM (1 mL). The filtrate is concentrated under vacuum and the residue (92 mg) is HPLC (column: X-tellurra C-18 30 × 1.9 cm; mobile phase: 10 mM ammonium acetate solution / acetonitrile from 50/50 to 10/90 in 12 minutes; flow rate = 7 mL / min; λ = 225 nm) to obtain the title compound (48 mg).
NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.5-3.2 (M, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.6- 2.36 (m, 4H); 2.5 ( m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 535 [M + H] ^< +>.
HPLC: Column: X-Terra C-18 25x0.48 cm; Mobile phase: 10 mM ammonium acetate solution / acetonitrile from 50/50 to 10/90 in 12 minutes; Flow rate = 0.8 mL / min; λ = 225 nm; Retention time : 9.7 minutes.

Example 47
4- (4-acetylpiperazino) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide (47a; diastereomer 1)
And 4- (4-acetylpiperazino) -1- (4-fluoro-2-methyl-phenyl) -piperidine-2-carboxylic acid (3,5-ditrifluoromethyl-benzyl) -methylamide (47a-diastereo Mar 2)

Example 46 (45 mg) was purified by chiral HPLC (column: Chiralcel OD 25 × 2.0 cm; mobile phase: n-hexane / EtOH 80/20; flow rate: 7 mL / min; λ = 225 nm):
1. Example 47a (18 mg; retention time: 19.7 minutes)
2. Example 47b (17 mg; retention time: 31.1 minutes)

Example 47a
NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.5-3.2 (M, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.6- 2.36 (m, 4H); 2.5 ( m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 535 [M + H] ^< +>.
HPLC: column chiral cell OD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 80/20; flow rate: 1 mL / min; λ225 nm; retention time 7.2 minutes.

Example 47b
NMR (d ₆ -DMSO): δ (ppm) 7.92 (s, 1H); 7.55 (s, 2H); 7.07 (dd, 1H); 6.91 (d, 1H); 74 (td, 1H); 4.74 (bm, 1H); 4.24 (bm, 2H); 4.1 (bs, 1H); 3.6 (m, 4H); 3.5-3.2 (M, 4H); 3.3 (m, 2H); 3.11 (s, 3H); 2.92 (bs, 1H); 2.6- 2.36 (m, 4H); 2.5 ( m, 4H); 2.27 (s, 3H); 2.00 (m, 1H); 1.80 (m, 1H); 1.56 (m, 2H).
MS (ES / +) m / z = 535 [M + H] ^< +>.
HPLC: column chiral cell OD 25 x 0.46 cm; mobile phase: n-hexane / EtOH 80/20; flow rate: 1 mL / min; [lambda] = 225 nm; retention time 11.7 minutes.

Pharmaceutical Examples A. Tablet active ingredient 10.0mg
PVP 9mg
Microcrystalline cellulose 266mg
Sodium starch glycolate 12mg
Magnesium stearate 3mg

Active ingredient 50mg
PVP 9mg
Microcrystalline cellulose 226mg
Sodium starch glycolate 12mg
Magnesium stearate 3mg

The active ingredient is blended with other ingredients. The blend can be compressed using a suitable punch to form a tablet. Tablets may be coated using conventional techniques and coatings.

B. Capsule active ingredient 25.0mg
(1-100mg)
Microcrystalline cellulose

The active ingredient is blended with microcrystalline cellulose and then filled into suitable capsules.

C. Injection active ingredient 2-20mg / ml
PH 3.5 (3.0-4.0) buffer suitable for injection Suitable amount up to 10 mL (eg sterile citrate buffer or NaCl 0.9% for injection)

  The formulation can be packaged in glass or plastic vials or ampoules. The formulation can be administered, for example, by bolus injection or infusion after dilution with D5W or 0.9% NaCl.

NK ₁ receptor binding affinity method for measuring in vitro the ability of a compound to replace [ ³ H] -Substance P (SP) from a recombinant human NK ₁ receptor expressed in a Chinese hamster ovary (CHO) cell membrane Was used to measure the affinity of the compounds of the present invention for the NK ₁ receptor. Its affinity value (pKi) is expressed as the negative logarithm of the inhibition constant (Ki) of the ligand being replaced.
The average value of pKi values obtained by measuring at least twice with the representative compound of the present invention is in the range of 8.24 and 10.21.

Claims (17)

Formula (I):

(I)
[Where:
R is halogen or C _1-4 alkyl;
R ₁ is hydrogen or C _1-4 alkyl;
R ₂ is hydrogen, C _1-4 alkyl, or R ₂ together with R ₃ represents C _3-7 cycloalkyl;
R ₃ is hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-6 alkenyl; or R ₁ and R ₃ together with the nitrogen and carbon atoms to which they are attached respectively, Represents a 6-membered heterocyclic group;
R ₄ is trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethoxy or halogen;
R ₅ is hydrogen and R ₆ is NR ₇ R ₈ or R ₅ is NR ₈ R ₉ and R ₆ is hydrogen;
R ₇ is hydrogen or C _1-4 alkyl, or R ₇ and R ₈ together with the nitrogen to which they are attached represent an oxygen-containing saturated 5- to 7-membered heterocyclic group;
R ₈ is saturated 5 to 1 containing 1 to 3 heteroatoms selected from hydrogen, phenyl, C _3-7 cycloalkyl, (CH ₂ ) _p C (O) NR ₁₀ R ₁₁ , oxygen, sulfur and nitrogen. Selected from 7-membered heterocyclic groups (optionally substituted with C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl), oxygen, sulfur and nitrogen 5-membered heteroaryl groups containing 1 to 3 heteroatoms (optionally substituted with C _1-4 alkyl S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl) Or R ₈ is a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms (C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 Optionally substituted with alkyl); Other _(may be _{C 1-4} alkyl, optionally substituted with C _{(O) C 1-4} alkyl or halogen) _{R 8} is fluorine, phenyl, = _{O, C 3-7} cycloalkyl, hydroxy, amino, dimethyl A C _1-6 alkyl group optionally substituted by 1 or 2 groups selected from amino, aminocarbonyl, C _1-4 alkoxy or trifluoromethyl;
R ₉ is hydrogen, C _1-4 alkyl, or R ₉ and R ₈ together with the nitrogen to which they are attached contain another heteroatom selected from oxygen, sulfur and nitrogen. _{1 selected} from C _1-4 alkyl, ═O, S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl or C (O) C _1-4 alkyl. Or a 5- to 7-membered heterocyclic group optionally substituted by 2 groups;
R ₁₀ and R ₁₁ are independently hydrogen or a C _1-4 alkyl group;
X is a nitrogen atom and Y is CH or X is CH and Y is nitrogen;
m is 0 or an integer from 1 to 3;
n is an integer from 1 to 3;
p is 0, 1 or 2]
Or a pharmaceutically acceptable salt and solvate thereof. R ₆ is NR ₇ R ₈ and R ₅ is hydrogen and Y is nitrogen and X is CH or R ₆ is hydrogen and R ₅ is NR ₈ R ₉ The compound of claim 1, wherein Y is CH and X is nitrogen. 3. A compound according to claim 1 or claim 2 wherein R is a halogen (e.g. fluorine) and / or a _C1-4 alkyl (e.g. methyl) group and m is 0 or an integer from 1 to 2. The compound according to any one of claims 1 to 3, wherein R ₁ is a methyl group. The compound according to any one of claims 1 to 4, wherein R ₂ is a hydrogen atom or a methyl group. The compound according to any one of claims 1 to 5, wherein R ₃ is a hydrogen atom or a methyl group. The compound according to any one of claims 1 to 6, wherein R ₄ is a trifluoromethyl group and / or a halogen (ie, chlorine), and n is 2. R ₅ is hydrogen, NH (C _3-7 cycloalkyl), NH (C _{1-4 alkylC 3-7} cycloalkyl), 1-piperazinyl (C _1-4 alkyl, ═O, S (O) ₂ C _{1 -4} alkyl, optionally substituted by 1 or 2 groups selected from C (O) C _3-7 cycloalkyl or C (O) C _1-4 alkyl); piperidyl (C _1-4 alkyl) 8. A compound according to any of claims 1 to 7 which is optionally substituted by 1 or 2 groups selected from = O) or morpholino. R ₆ is hydrogen, N (C _1-6 alkyl) ₂ , NH (C _1-6 alkyl), NH (CH ₂ ) _p C (O) NR ₁₀ R ₁₁ (wherein p is 1 or 2, R ₉ and R ₁₀ are independently hydrogen or methyl), NH (C _1-6 alkyltrifluoromethyl), NH (C _1-6 alkylC _1-4 alkoxy), NH (C _1-6 Arukirufu' element), _{N (C 1-6 alkyl) (C 1-6} Arukirufu' element), NH _{(C 1-6} alkylphenyl), NH _{(C 3-7} cycloalkyl), NH (piperidyl), NH _{(C 1 -6} alkylaminocarbonyl), NH _{(C 1-6} alkyl-1,3-dioxolanyl) or morpholino compound according to any one of claims 1 to 8 in place. R ₆ is NR ₇ R ₈ and R ₅ is hydrogen and Y is nitrogen and X is CH or R ₆ is hydrogen and R ₅ is NR ₈ R ₉ Y is CH and X is nitrogen;
R ₇ is hydrogen or methyl;
R ₈ is methyl, ethyl, dimethylpropyl, cyclopropyl, cyclobutyl, CH ₂ C (O) NH ₂ , piperidinyl, 1-methyl-piperidinyl, or phenyl, cyclopropyl, 4-acetyl-piperazino, fluorine, methoxy, trifluoro Methyl substituted with a group selected from methyl and 1.3-dioxolanyl;
R ₉ is hydrogen or methyl;
R ₉ and R ₈ together with the nitrogen to which they are attached are 1-piperazinyl, acetyl-1-piperazinyl, morpholino;
R ₇ and R ₈ together with their bound nitrogen are morpholinos;
R is independently fluorine or methyl;
R ₄ is trifluoromethyl and / or chlorine;
m is 1 or 2;
10. The compound according to any one of claims 1 to 9, wherein n is 2. 4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3,5-bis-trifluoromethyl -Phenyl) -ethyl] -methylamide hydrochloride;
4- (S) -Dimethylamino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl) -methylamide hydrochloride ;
4- (S)-(2-Fluoroethyl) -amino-2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid [1- (R)-(3.5 -Bis) -trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride;
4- (S)-(2-Fluoro-ethylamino) -2- (R)-(4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl- (Benzyl) -methylamide hydrochloride.
11. A compound according to any one of claims 1 to 10 selected from.   12. A compound according to any one of claims 1 to 11 for use in therapy.   Use of a compound according to any of claims 1 to 11 in the manufacture of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins.   Use of a compound according to any of claims 1 to 11 in the treatment of tachykinin mediated conditions including substance P and other neurokinins.   A pharmaceutical composition comprising a compound according to any of claims 1 to 11 and one or more pharmaceutically acceptable carriers or excipients in admixture.   12. A method of treating mammals, including humans, particularly in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins, comprising administering an effective amount of a compound according to any of claims 1-11. A method comprising: Formula (II):

(II)
[Wherein R ₁₂ is ═O and R ₁₃ is hydrogen, or R ₁₂ is hydrogen and R ₁₃ is ═O]
In the presence of a suitable reducing agent of the metal (III):
NR ₅ R ₆ (III)
Subjected to reductive N-alkylation using an amine derivative of the formula, followed by one or more of the following steps if necessary or desired:
i) removing any protecting groups;
12. A compound according to any one of claims 1 to 11, comprising subjecting ii) isolating the compound as a salt or solvate thereof to divide the compound of formula (I) or a derivative thereof into its enantiomers. The manufacturing method.